CA2277123A1 - System and method for medical language extraction and encoding - Google Patents

System and method for medical language extraction and encoding Download PDF

Info

Publication number
CA2277123A1
CA2277123A1 CA002277123A CA2277123A CA2277123A1 CA 2277123 A1 CA2277123 A1 CA 2277123A1 CA 002277123 A CA002277123 A CA 002277123A CA 2277123 A CA2277123 A CA 2277123A CA 2277123 A1 CA2277123 A1 CA 2277123A1
Authority
CA
Canada
Prior art keywords
referring
indicative
phrase
parsing
parameter
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002277123A
Other languages
French (fr)
Inventor
Carol Friedman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Columbia University of New York
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2277123A1 publication Critical patent/CA2277123A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • GPHYSICS
    • G06COMPUTING; CALCULATING OR COUNTING
    • G06FELECTRIC DIGITAL DATA PROCESSING
    • G06F40/00Handling natural language data
    • G06F40/20Natural language analysis
    • G06F40/279Recognition of textual entities
    • GPHYSICS
    • G06COMPUTING; CALCULATING OR COUNTING
    • G06FELECTRIC DIGITAL DATA PROCESSING
    • G06F40/00Handling natural language data
    • G06F40/20Natural language analysis
    • G06F40/205Parsing
    • GPHYSICS
    • G06COMPUTING; CALCULATING OR COUNTING
    • G06FELECTRIC DIGITAL DATA PROCESSING
    • G06F40/00Handling natural language data
    • G06F40/20Natural language analysis
    • G06F40/279Recognition of textual entities
    • G06F40/289Phrasal analysis, e.g. finite state techniques or chunking
    • GPHYSICS
    • G06COMPUTING; CALCULATING OR COUNTING
    • G06FELECTRIC DIGITAL DATA PROCESSING
    • G06F40/00Handling natural language data
    • G06F40/30Semantic analysis
    • G06F40/35Discourse or dialogue representation
    • GPHYSICS
    • G16INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16HHEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H10/00ICT specially adapted for the handling or processing of patient-related medical or healthcare data
    • G16H10/60ICT specially adapted for the handling or processing of patient-related medical or healthcare data for patient-specific data, e.g. for electronic patient records

Abstract

In computerized processing of natural-language medical/clinical data including phrase parsing and regularizing, parameters are referred to whose values can be specified by the user. Thus, a computerized system can be provided with versatility, for the processing of the data originating in diverse domains, for example. Further to a parser (12) and a regularizer (13), the system includes a preprocessor (11), output filters (14) and an encoding mechanism (15).

Description

WO 98/19253 PCT/LTS9~119362 System and Method for Medical Lang~~e Extraction and Encoding This invention relates to natural language processing and, more specifically, to computerized processing of natural-language phrases found in medical/clinical data.
Clinical information as expressed by health care personnel is typically provided in natural language, e.g., in English. But, while phrases in natural language are convenient in interpersonal communication, the same typically does not apply to computerized applications such as automated quality assurance, clinical decision support, patient management, outcome studies, administration, research and literature searching. Even where clinical data is available in electronic or computer-readable form, the data may remain inaccessible to computerized systems because of its form as narrative text.
For computerized applications, methods and systems have been developed for producing standardized, encoded representations of clinical information from natural-language sources such as findings from examinations, medical history, progress notes, and discharge summaries. Special-purpose techniques have been used in different domains, e.g., general and specialized pathology, radiology, and surgery discharge reports.
Of particular further interest is a general approach which is based on concepts and techniques described in the following papers:
C. Friedman et al., "A Conceptual Model for Clinical Radiology Reports". In: C. Safran, ed., Seventeept~~~nosium for Computer Applications in Medical Care, New York, McGraw-Hill, March 1994, pp. 829-833;
C. Friedman et al., "A General Natural-Language Text Processor for Clinical Radiology", 3ournal of the American Medical Informatics Association Vol 1 (April 1994), pp. 161-174;
C. Friedman et al., "A Schema for Representing Medical Language Applied to Clinical Radiology", Journal of the American Medical Informatics Association. Vol. 1 (June 1994), pp. 233-248;
C. Friedman et al., "Natural Language Processing in an Operational Clinical Information System", Natural Lang,~age Engineering. Vol. 1 (March 1995), pp. 83-106.
~ummarv of the Invention A preferred method for computerized processing of natural-language medical/clinical data includes basic steps here designated as phrase parsing and regularizing and, optionally, code selection. Further included, preferably, is a step of pre-processing prior to phrase parsing, and a step of output filtering. Output can be generated in the form of a printout, as a monitor display, as a database entry, or via the "information highway", for example.
In processing, one or several parameters are referred to. The parameters are associated with options. To choose an option, the appropriate value is assigned to the parameter. A parameter can have a value by default. Of particular importance is the inclusion of a parameter which is associated with the medical/clinical domain or subfield of the input data. Other parameters may be associated with the level of parsing accuracy desired, whether code selection is desired, the type of filtering, or the format of the output.
The method can be expressed in a high-level computer language such as Prolog, for example, for execution as a system on a suitable general-purpose computer. In the following, the method and the system will be referred to by the acronym MedLEE, short for Medical Language Extraction and Encoding.
Brief Description of the Drawing Fig. 1 is a diagram of the MedLEE system or "server".
Fig. 2 is a diagram of a system or application which has an interface for MedLee.
An Appendix hereto includes a printout of computer source code for a portion of MedLEE.
Detailed Description of Preferred Embodiments A natural-language phrase included in medical/clinical data is understood as a delimited string comprising natural-language terms or words.
The string is computer-readable as obtained, e.g., from a pre-existing database, or from keyboard input, optical scanning of typed or handwritten text, or processed voice input. The delimiter may be a period, a semicolon, an end-of message signal, a new-paragraph signal, or any other suitable symbol recognizable for this purpose.
Within the phrase, the terms are separated by another delimiter, e.g., a blank or another suitable symbol.
As a result of phrase parsing, terms in a natural-language phrase are classified, e.g., as referring to a body part, a body location, a clinical condition or a degree of certainty of a clinical condition, and the relationships between the terms are established and represented in a standard form. For example, in the phrase "moderate cardiac enlargement", "moderate" is related to "enlargement" and cardiac is also related to "enlargement".
In the interest of versatility and applicability of the system to different domains, parsing is domain specific as a function of the value assigned to a parameter which the system refers to in parsing. Depending on the value of the domain parameter, the appropriate rules can be referred to in parsing by the system.
While parsing may be based primarily on semantics or meaning, use of syntactic or grammatical information is not precluded.
Regularizing involves bringing together terms which may be discontiguous in a natural-language phrase but which belong together conceptually.
Regular forms or composites are obtained. Regularizing may involve reference to a separate knowledge base. For example, from each of the phrases "heart is enlarged", "enlarged heart", "heart shows enlargement" and "cardiac enlargement", a regularizes can generate "enlarged heart".
In code selection, which is optional, a common, unique vocabulary term or code is assigned to each regular term by reference to yet another knowledge base which may also be chosen domain specific. For example, in the domain of X-ray diagnostics, the term "cystic disease" has a different meaning as compared with the domain of mammography.
Fig. 1 shows a preprocessor module 11 by which natural-language input text is received. The preprocessor uses the lexicon knowledge base 101 and handles abbreviations, which may be domain dependent. With the domain parameter properly set, the preprocessor refers to the proper knowledge base. For example, depending on the domain, the abbreviation "P.E." can be understood as physical examination or as pleural effusion. Also, the preprocessor determines phrase or sentence boundaries, and generates a list form for each phrase for further processing by the parser module 12.
The parser module 12 also uses the lexicon 101, and a grammar module 102 to generate intermediate target forms. Thus, in addition to parsing of complete phrases, subphrase parsing can be used to advantage where highest accuracy is not required. In case a phrase cannot be parsed in its entirety, one or several attempts can be made to parse a portion of the phrase for obtaining useful information in spite of some uncertainty. For example, subphrase parsing can be used in surveying discharge summaries.
With the parsed forms as input, and using mapping information 103, the phrase regularizes 13 composes regular terms as described above.
From the regularized phrases, the filter module 14 deletes information on the basis of parameter settings. For example, a parameter can be set to call for removal of negative findings.
The encoder module 15 uses a table of codes 104 to translate the regularized forms into unique concepts which are compatible with a clinical controlled vocabulary.
Fig. 2 shows an interface module 21, and the MedLee system 22 of Fig. 1. The interface module 21 may be domain-specific, and it may serve, e.g., to separate formatted sections from non-formatted sections in a report. Also, the interface 22 may serve to pass chosen parameter values to the MedLEE system 22 and to pass output from the MedLEE system. For example, such an interface can be designed for communication over the World-Wide Web or a local network, for input to or output from MedLEE.
Conveniently, each module is software-implemented and stored in random-access memory of a suitable computer, e.g., a work-station computer.
The software can be in the form of executable object code, obtained, e.g., by compiling -from source code. Source code interpretation is not precluded. Source code can be in the form of sequence-controlled instructions as in Fortran, Pascal or "C", for example.
Alternatively a rule-based system can be used such a Prolog, where suitable sequencing is chosen by the system at run-time.
An illustrative portion of the MedLEE system is shown in the Appendix in the form of a Prolog source listing with comments. The following is further to the comments.
Process Bents with get inputsents, process sects and outputresults reads in an input stream, processes sections of the input stream according to parameter settings, and produces output according to the settings. Among parameters supplied to Process_sents are the following: Exam {specifying the domain), Mode (specifying the parsing mode), Amount (specifying the type of filtering), Type (specifying the output format) and Protocol (html or plain). Process_sents is called by another predicate, after user-specified parameters have been processed.
Process sects with get section and parse sentences gets each section and generates intermediate output for the sentences in each section.
Outputresults with removefromtarg, write, writelines, markupsents and outputhl7 filters output if appropriate, produces output in the appropriate format and optionally including formats tags for selected words of the original sentence, and produces error messages and an end-of output message.
Setargs sets arguments or parameter values based on user input or by default.
Removefromtarg filters formatted output by leaving only positive .
clinical information and by removing negative findings from the formatted output.
Another parameter, parc, removes findings associated with past information from the formatted output. Any number of different filters can be included as suitable.
Writelines produces one line per finding, in list format.
Writeindentform and writeindentform2 produce output in indented form.
Markupsents envelopes the original sentence with tags so that the clinical information is highlighted. Different types of information can be highlighted in different colors by use of an appropriate browser program such as Netscape, for example.
Outputhl7 converts output to appropriate form for database (xformtodb) and writes out the form in h17 in coded format. This process uses synonym knowledge and an encoding knowledge base.

_ '7 _ APPENDIX

-g ..
d b m m ro N

i a O

C w ~ t~7 it .~ a~

O d v~ m y i C
~ y ~ .,. ~ O
, ,.
., p b y O ~..~ y m m y m a~

y ' y ~ m ::

, , C w G m G
d . O CT
.
'C

y WC
y y b 4 w ~ p d1 d & ~ w C C U

G ~ O m ~ w O, -- w G, f. w ro ro m >, a a ar ~ y d b ai ry C d m O ~ ~ . ~ -~
x .. 0 a. s.1 ~ ~. ro -~ y 3 1 d .r y w O
~

'a 0 O w 4 ~ y ~ O

'~

y o .
, ~ -~ -r l o D C w C . w O ..~ a .1 -i O d O it ... ..r .-~
w ..., y .,., O
E ~ E m i y ~

~ v y E O
.
.

m m ~G r ' p .
~ ro w y ..

O ~ - ~ o O Or7 C

w B m 01 it .
~

drdrardrdPdP 1 o v m '' 'oroc ro ~.
m o .... . a ( ~ ~
I
. .-~

w -. ~ .r w ... . ~ ~
'~ '~ "i i E

m m . u O ~.
r H m 1~ ~'"_ c " ~' ~ m~ . 3 ~ v~ m a ~ ~
a 0 s..~ ( . y m x ai . . ~.. (. V -i i W
~. ro s ae ... i ii p _ ~

..~ _ _. y _ _ . m a _ (..) e C"im r H m C~ ! C~
~h . ~ ai.
\ \C ~
I~ O
-~ .

G t V 1r ' C . . y ~ C ~ ~ ~. O C EO.

o ... ~ ~ ~ ~
~ y a .,., pv .~ y r, f A C ~
~ E
~

. m o d O . y G.
p d ~ rtl Ir pv w C .-. / ro ~ y is / \ w y d y p~ m 1, p .. y w .-, U m .... C C C y C A ~ CI >.e C y .,a y .-. 0 ~
.. U
m 0 O r~
O .., ~- E

41 C 0 a C
..a ..~ 01 ..~ ~ . C al O it 7 i b ., C O O ~ m ~ r~
C a a p A 0~ m v a ... O m lr a! O .,. U
) b N a~
~-~. 4 i! ~ d ~ a,r O
~w a m O~ al E ~ C~ C
~ a~

ww ~ C y > >d C ~
u~p v~u ~ y ~ C

a .. I
i x~o .. r.. m . ~ yy .~N a .i l ~6 a maonr ... ... w~ro~oroaa o ~ m w L
. .. m m .

. ~.) y y y .- y ~- ~
C C . . U C ~ C ~ y l V V a ~ m U y U a.~ V y O a m ~f 3 D .1 d C~7 nr .a a m ~ 7 0 o ..r b la N L rp m 01 1 .a 1 r ip .~ y d O O O ~ 8 .C '~ ~ / 4 ~p aJ 4 U
B 41 Ir O 1r y 1 m 01 fr v V U
1 1 y s a .-) ..i 'r 'C : ro 3 v~ o y ai m s~ m y i1 O
~ ro m m .~ m ~r y O a v 1 m of a ~ O
-~ .se C C a m d m d m o m p~ p, y 3 O
C G m d m s.

0 a w ~ y ~ ~ b Imo 4 a t~ o d m E sa p O O 'O 4 o ~ O

~~ O O

. . . . v V !r ar d, " a o, SUBSTITUTE SHEET (RULE 26) WO 98!19253 PCTIUS97/19362 x w v a w a 'v a . s ai o ~ m -. n y a n m C S. L
o ti ~ 0 v b s ~O

7 E - ~ a y p m p, w n r e C
i .
C

O ~
~ ~

O7 m x N v'C

VLy > C~ v V v 01 C y tw O y UC ~. C ~! C U O N d 7 --i 9 -n n ~p ..i -r m a~
dI m d o C .~ 47 m B ar U rr e1 y ~ a d 0N y x .-. c1 y ~ 0 s .

-~ .~ a -r w ~ , ~ y ~ C
~

0 d ay a dr y' ~ a' Gy ~ a ' ~

( a ..
y a o a ~ :
o a ~

w c ., :. w .. y o r ~C -i - E C -r .r .~ 1r I .-r E~f a ay, .r O~ 1r d itC ~ .-i 0 ~ 41 J IQ.~
. t ~ ~
'A

7~ C ~ ~ Z C
C m b I ~

~

.-~~ 47 ~ m I O Ir -~ V
y m ... w tr t a er a w n, o ~ 1 I O A J.1 fl[ "a 4 4a a C a 3 d ~ a C
m s.

d,.. 3 a d w m o a -~ w a C -~ m .r.. o n o~ d ... v m dr x c ..~
d .rO w O = v O
~ ~

~ p r~
>. .

yO y y ~ C a C o - ~ -- H d .~

~y .a 0 ~ Or O ~ O O d1 ~ - ~ C

V 1! C ~i C: ..1 OO y n d N "

f ~ v. v rr a~ r.1 dI . .
r ~ 'C a O ..
~. y ~

jc. ~o ..~ - b r.~ e 1 y .c 4 ~ ...m m m .-~.- n v b y a a ~
O

aw-, n -~o d..~ 6 ., . $, ~..c u.. y a 'Ca d 111 .1 rl .. --1-1 ...1a W ., a .~ ..) ~
O.-r ~ d C ~ d y ~ ~
do v .-W m w x.-~ o w .c w cs .a cs 1-. o ~
O ..ia x I s. w ~ w ~
aiV 7 > ~ 14r ~ ~ C a~
E. ~ O ~ ~ d ova ~ ~
v .. it C
a ~ ~ ~ -~ ~ ~ d dm . 01 ~ ~ . b O
~ ~ y :
~ 8 m...) ,, a p y a x 4 p w _ a w .,- ~ ... ~ x ~ s.
~ r~ C ~r $ ~ y g..r ~ ,~ ,~ t . v~ v~ A v ~ C
a OO ~ ~~vV O ~ ~On ~A ~dpla . C ' GCV ~a~ ~

a ~ .~
x~ ...)a r. . ,~ x ae ~ a . ..a n~d ..w . . -~ s .a y o y~ . c ~ a v a a.,...~,..., a a v a .y .r .-~ a ro ~ O
s)w 4 al y ~ ,C '~J ~C
~ L dl 1 a G
y GI
.r .-~
~r y v a~
/ ~

a~G. 3 ~ ~ w a U O V y ~ O -~ y y U
-~ y ~ ;
y CC U Ir ~ a,r lO b 4 O L 4 ar ..r 1a ip 1.~ 4 CI

d-~ dr ~ 3 .~ .. w w or -- dr 3 3 ar a d ~
; C ~ o ..

el a m ~ o )y .- .. p ; ... .. a m ~ .. t v n ~

ma E w w ro a ro w b rr ~.
y o x o v n d SUBSTITUTE SHEET (RULE 26) L O 'C

L

y m O

~

m O

w a w ~

O O o d O a w "'' ~ o o a o a r , ~
p r -r ~ a ~ ~ ~ ~ c - y a ~ ~ ' a a . dr o . ~
u t C ~r y y ~ o ~ a i a ~. o s C o ~; d a . ~

., f y w t~ t7 .~ .r . C .r p ~ ., w 01 - .- w >
a o ~ _' b v' O a 0 G C
o L m a C al ~C t7 C ..
.~ V w a ,.y ~ N ~ a a ~
d U .. .r - .. o y y 11 Ci~1 C a I

w A m o -a C -a w m o y ~

c G v .a a~ b y .r b G~ -~ y ~i 4 a C

> ~5 -r d~dllb .fir G ~..mi p w A ~ y ~ ~ ~ ~ y ...iV o ov. w ~

w m ~ ~ y a ~ ~: d 4 m ~
O

o c o . .i C m y y .r 7 O y, m w ...
~ G -..~ y at O ie -a fr y O yr m ~
E D w '~' .-~ w ~
~ -~ ~ y ~ 0 .~ .
O -a ~i o i 4 (~ .~ cs.
x p, I .

8 ..) . ~e ai a ~ y y . ~ y m ~ ~ o p y a .-~i 6 i y a m dr o w or a o ~ .~ 4. y r fa.
U .G .~ r1 .v ~
o w y 6 00 ~ .a m b ~ .a , a , ..
. cG y I i _ ~ ~ w Z ~ ~ ~r x ., ...
~r . . ~. _) .-y p r.. m o ~ c.~ x y m y ...
i ~ m y m m E y ~i -- y m y , m ...
o .~ m m a .r . 0G _ o m , Via.o -a a~
,. a -a ~ G i ~r o G - ~ o I a a 0 ao .., .. ... , . y -~ a w -~ a o d ca 'v t7 ~. -o , b --. G . e~ .~ . +~ O y o m ~ 0 m m ~ ~ y y w N 8 ~ o~ ~

y ~ ~r -. C d ~ ~ ~, .~ ~
to E ~ ~ SB~. C D C , .1 y i . b r . d o x -y ~ 0 ..- . o C y w m E , .,, I -a - . r~, O , o y o t~ m ~ y ~ p n m N ~
a . p d .r ..~ X . B y . ..~ O ... .
..aC , C . V .
y y ~ ..
o .1 m D m N y c ... .-.O'~ y 0 ~ ~ a ~ y i N o . E ..~ ~
O c G . , ~ ~- a m y x y x w ~ 8 y a ...~r a . (-.
m .r W y o w p. , o E I -~ C m y .-r o A ~- o a1 a o O . w -a , y m .~
m o C
m . ~. m w m o o x y ~o m ~ O v y o y .. ~ ~ 'G y C o y ~ C o y ~ ~, I vWt oG at fa. m 'C A O v m ~
.r ._. rr m m G m C QI U
D

m , a -~ G _ y ~ . o o d C
m a O -~ a v C
o C

_ w y o I o ' m .C . 'o w x ~o y y .~ .-~ E - ~ o ~
a y ~

.r C 1. . r y ~ 0 01 C~ ..a G ~ II
U .-r p yt C w at .-i y C 1, ~

o al o . C V y .-~ C 8 .-i o O v 0 ~ -. m o o O ~p C
0 o .-4 _ .~ E ..., ..r N G m w 'C w O ~ ~ m "0 E-~ i0 GI y m c tn E ~ y ..- O ts, m ~ y -. y C y . d o ~ m ~- .- m m l G .r c m "J m w m y I ""'"' m ~ U y 7 0 ~
w at ~ y V I -~~
~
~

d y o y b U m y1 ' m p 0 W0 4 a a d m iJ ~ rW GI .-r ~ ~ s~ a o m 7 ~ 'C1 "0 a y s. o y o. y o a ~ 'C o s~ m y ae d o o a m o d C C C m a y m ~ b V o o o C o m y 4 ~

1r y .C m I V y o 0 0 .~ o o m O O
O G m m y 0 m m o ~o .

y O ~ a a ~ m s~ a 6 O l v ~ ~ a y ~o a d l ~ a m s~
3 d 4 ~ ~

m o O .
w b .. o v~ c. -- - a o m y v b d m A
a m n~ , a o~

G
~o a a o a a O m ~' y O

dP o dr dr A o, SUBSTITUTE SHEET (RULE 26) y a .. ~r > >

O

w o ..

y _. a y d ~~ p O

~ ' O

y : O
~

-., y y ~ j1 y . y .r -_ e~e ' 'v ~
ova 0 O a C ai ~E. a x t ~ ..e C

v ay~ ~ ..r s y Z ai e - w o ~' c o a s ~ ' ~ I
.~

l s a o v c a ab s ~ ~ y~ :
e .
w 4 A ~ $o 0 y w y I
a ~

r ~ ~ O O O a~ ar 0 a! w G y C

_ ' C ~ d b ~ v ~ u . w .~
"

~ ~ y C :
~
a O y O~ r W
w O ~ 4 1 G w C ~
s. 8 . O
E- w y ~ C
~
~

d a-. .r w a v~ : ~~-~ m r o ' ~

~ , .r g C ,., o ar A .,.
.-~ y E w -a r~ E
w O y ..
w .r r.~ ~ O ~ it ~.. ai ~ a a~ ~
. ~. r w a ~ ~ . O
.) ~ V O~ d m ~ ~ 1 ~ a ~
1 ~ a ~
E

x o .0 '''' ':.. ~ ~
g~ a o ~ -~ O ~ a . c G o ~
b > O dr ~

y ; .i Ia a~
.

v _ ~

~u '~CO~-~_._ 3~-3~ a ' "' ~ C~
' ~

ca. ~ ~ . a .. . O
E- C
~ -a ( _ - ~ . ~ . n a , c ") y y G C E a 1 v ~ - .r n 41 - a . b . ar it r of > C i .r w ~ 01 t ~1 . r.r C . ai .r ~ y 6 .r ..~ w O C ~
a O O v i t ~o - ..r ro a y ar ec ro ~ .-~ ov. t ..) 4 ,u r ~ .~ .~' ~ ., o C C r -w 3 w '' w v a y .~ w ~ s -~
.r . v rr a~ C ., r ~ v .

1 p "'.~rr C ~ t ~ t 1 ~' ~ L ..- ~ ~ y ''' a w r y a o~ y a y .
c ~ r ~ ~ 1 1 y d a .

~ ' y ~ 1 y ~ _ .,. ...
p ~ .., 0 s ~ ~ 01 G y I

, ~
, p y ~~
u 3 ~
O

.c H
. 0 E

y v y a rJ

O

SUBSTITUTE SHEET (RULE 26) i _g _ c a n N A

x \ f v f J

s O

m f Z

TJ

O m 9 3 'C a L a 'C O m 3 y -C C C

..~ C r.

w a1 Q7 CI C - n ..~ - t~
C

C w ..r x a D m \ a 'C -. v a C

n C ''-' . s m N ~ d 'Q s 1 m t V a i m a n * .,., C sr --OG a w .r ro m ~

x * o ro c. 1 ~
t v f ~p o E i rt -.
p~

C p p y n.
a .,.

~ p ~ ~ ~
'- m ~

t. i.. .-~ .r .

0 0 3 G C .a .., r, ~

., ., .~ ... ..) m ~
L ..~ ro i. p (., .. r. ~- w - ar ro a v a ro o ro b A o m ... m cs. m . .-, a .~

U U V 1 C ~C1 ro y ..i m .
.-~

p .-) 1. f f.r . A C III
y! y f0 w . w L. w O a t ro dl a w ii C
U

o ... ~ o 3 a y n. -- w m . N
C p o .

'O '-' C ' a C \ t C ~p 3 't7 t 0D
'0 G C e7 ~ 'p 01m C 1 c4 ~

D 1 .~. C! 7 - W rn D / \ rt O
C C r-~

.o a r~- c a .~) awr, v ai o - ~ o -~ 0 5 a a o o ro c w ro ..a w ..a ~ C w ~ --o ., a 'v a.
~ m a, ..t d .r .
.... w ~ "'~ d ~ w ~ ~
~ ~

w ~p w ~. .. .-. . . -.,- s C -v r C

C C C o - C a CI L iJ .. -..
y tl 3 ~ w ~-Li ~J ~ C - D . C o) Li C y ~ it 5 t ~
r p~ ~ . ... o I m o t y 4 ~ n y y d o -i s ~. v ito . o~ pv t a N m w t t b~ v p~ m ~ ..) C ~ ..
.~ n f o x ~ tT
tT

o ac a n. -- -1 f o v y m ~ .-) ro t ~7 -~ -~ O
..~

m o m 1 r w m o x .. . ,c m a v f x n ... c c .r ..~

m m ,., . 1 a . I m o -~ . v~
. m ~ x t :c t 1 1 .C L ,~ ~. x w a ...) P
01 .. .r a dp v CT

m w ~ ~ 1 .G ..r y ~ v 1 ~
te L fr . 01 .m-~ . . :
r .. -~ l a a J !
~

fi '~ ~~ C ~ ~ ~
~
L

. .) ~ ~ CaI~~ ; m I
r r ~ dy .. O

.-~ s. U D D r~ .-i .-~ .i a ..~
., 3 3 3 .~ y o ~. 3 ~
y (..) it 1r i.l, (~. rr .-. ..) b ; (-.) lr .1 4 .-~
..-~
...y V ~ U . . -- e~ dr ... ro ~. 3 w 3 3 dr . .- er s dl~ ro . dr v ~
w ~ U ~ U y 3 do ar 3 3 y d' 3 ~ ~

SUBSTITUTE SHEET (RULE 26) WO 98/19253 PG"T/US97/19362 d w y C

d y y .~ y s.

3 GL ~ it y ' a o y ..C, '~
C ~
m O

_ ~
O
C ~

a ~ O
'~

~ ~ z ~ ~ ~ ~

,~, .e y m a w a p a ,w _ dra~ R ~ .,v', s " ae,g a m t L .1 GI

?, 'CJ li O Z

.~.~ 4 . C y ~ ~ ~ C p ~ g ~

-n C ~r o v ,~ a w a y i! o amp w ~ ~ C y m a "') y ,p C
t ~ m E .-~ y a ~ m O m p ~ ' ~' m a . V
C m a ~ r C C .-1 t 4 w >
~ m t t 3 ~ . "
,i y m GI m v ~ ~ C _ ~ ~ ~ p, "~ ~
m ~ ~ y u C -u~ ~.~ ~ ~

y ..
.
.
, a a r0 t w m O
m r0 C ~' y ~
ty~ O
tpl..mi~"'~.r 'v( a a ar ~ ..) c~) o ~ ' ~ ~ 'v a a n o ~ ~ y v ' ~ ~ p .~ 'v ~ c ~ ~ .~ ., ; v ,W ~ ..
~ f . ~' m ~
,, ~ 9 rr Iw w i O
~ w y R
m t w w d m C
~ .C ~ .i ~

m G ~ ~C '~ 4 ~
'' p r., y a c ~ C

~

C9 a y ~ 4 ..y, 1er ::
_. a m o .., p a ,w y C
~

, d a~
'V tym4 e m 3 ( ~...i ..
C O a aC b.
r..
, y y n ga r "',aO
7.-~
ao d~
~

r.. .., , a , b "'~
x y o , y y w y ti it o w ~ p O

04 C 41 t t C w y w ;,. ... a ~ .~ (.~', o ~ O w y C t y y y ., arwaarm o .. ~
~ apCCUZ aoo ;
"

E ~ , w er ~. w y y ~.. ~ O O
~ d .. w ~- b ..r y ...~
C

y .. ~ y y . 4 r O
.) ., ~
., y r ~
y . 0 C C d m w .-mr 1~ ""~
~

~ 3 3 ~ or E- ~
e p ~
y ~ a a O G C
~
~

es" tr7 y dP m "
dI 3 y ~
C .~ d -7 w ~ 4 t ~ ~
a '~ ~ y ~

d ~ a t y .~ y , .
v w >

o ro ~ ~ ~
y ) e er ~ ~ Q

~.
dr dr a~ p , ~
dr dr dr , s.
m ~ 5C o n ~ . p m . ~ b 01 4.., ,~ In $ O n. w ~ ar ~ ~ d~ d~ d~
d1 d1 dP dr ' d dr ~ ~ dr d' ~

SUBSTITUTE SHEET (RULE 26) v a a m y _ -~ ~ g 0 o r r a a~ v~

N N N N m m N

p O O yl ~o ~o to ~o ~o ~o m r r r r o 0 0 a r N N N N v v v ov - a N
C b w w ' - , m w y w o y . v~ oo w a v v v m o r1 n-1 N N m ~ tD
1~

m b C ' ~0 ~D ~0 ~O ~0 ~D
.. r A w r r r r O O O 4 w p~ ~ ~ N N N N a v ~ tp v v n a ~ 3 . . ( r a .- a D ( . . . . o ~ i aW C m ..~, p O, ~ ~
~ _ m m m .r G . v m m (C tl1 1(1 h N
w m N

w 7 m ~, ~~ .i N N ao ao ~ m vo 4 v~

C d tf 70~t ~ m r _ ~~~~ ooo~
~
~

. ~ r a r ~ ~u '~e ~ xNNNN
v v v c~

u e a ' ' ' v a -1 s w ni m o o . .
. v - ' y w .. . a .-) al ar - . .
4 y m .

41 .~1Ir ~1 ,G 01 01 ~! v N N
y 4 ~C O O 01 11 ~ w v ~ w ~ U ~ ~ N N f~1 eat lr b L' ~ W I1 01 r G G it y ~ y v wo ~o ~o mo ~o r a . an I -- wrrrr rrooor ' ~ O y O N N N N N N et v ~ ) t1 O

I y v ~
~ ' y ~ ~ -m m m C .~ m a m x y .
~

C ~ w ~ ' m - a .-) .-~ N N ov o~
m ~ ~ ..r .. vo vo v v p . m i0 N N N N N N n n , C r r tr et O

m m ..Gr O y 0 o ~ ~ o o ~ r ~
G .y-~ ~ O ~ y ~
~: r ~ 0 0 0 0 c --w V ~ ~ N N N N N N
v v ~? a!

x ~ ..~ y 'C nt .. _ ll ~

C~ C ad mV n~" Up~. >. m wC~ m ' ~ ' ' ' O O w m . a ~ .. ..
w 4 .-. Via ..
v) v ~ .
C ~ a ~

. ., . p o o ~ .r ao ea o . .t o r r N N
.

O ' ' ~ m y ~( N N N N N N N1 rf a N ~ m O O Q1 0~

m A d) 4 C! A a ~1 ~! 4 N N 10 ~D \D 1D
b V -~ ~ ' O m y . 10 ~D ~D t0 ~D ~0 fr m a w ~
al E- ~ ~ w . O C m 0 0 o c~ ~ r r r r m a v o 0 0 0 s m d a ~ '~ ~ ' O 0) w r1 'i N N N N N
y ~ i 4 C~ ' N d d v Q
~ b '~

> > y y -- o x a a 4 ~ ~. -a ...
a ~t m x d ,)~ ~ _ ' U Vi C ~ ~ C ~ y >, p ~ ~
v m ~ . ~ X t a C O~ ~
O ~ y mr O
O ~
y m n ., 0 ~ O
7 a ~

~ .co m sd a . ~ x ~' d o o E a ~ a ~ y ar ara v~ v ..~ y a7 ~ ~ w 4 x m L m d C O C O w ~.
m v m p x ~ U

. , a F E yw .t 4 O o~
~o I I~~ 41 I i l C
x ~

O '- y y y . ,G dP E
M y y y y y d ~-d o m v m ar a a ar o . m m ar o. ~ a m o ro y w a n m ~

A
.:' a yl yl a x x d1 d~dr a l d~ d' C
d1 l o SUBSTITUTE SHEET (RULE 26) WO 98/19253 PCT/US97i19362 N N (f1 tf1 1I1 N

O ~r h s~ a N

N O

', .-; r ~ ~o vf1 'd N h u1 h 01 01 O ~0 N 1J
~

O O ~ h Lr O

V Q V~ N
~

v f~1 . . N C
.

O

v ~r ~o v h V
w ...

e1 r1 ~ W 0 N di O

O

O O ~ N .
~ p~

v v v v s v ~

~p rn b h ' !4 Lm-1 . N

8 . 1~
N

O O N 4 ~0 y' t'1 N v t"1 r1 m m v.i 1r \D a Ir Ir1 r-1 ~
M

0 o ~ o ~ w ~ o O o V ~.

a v v ~ y v v v v ~o v ov i G ~, ~o ~ s o .

6 v G a h h h w ~D
N N h N

ao ao o~ O a~ U ~ C
a~ v~ v c~
o~

0 0 0 - o w 0 0 0 ~

v v v - o v a V y v v v ao M

- y . v w C
O .

- p .v o a .. , 4 . ,~ w c eh in c~ v aD e~ y ei o~ : g ri ~0 ~0 ~0 . ~'-N N ~D tI1 m 1p ...

ao m o~ ao v h a o~ a~ ~.) h ao c, ococ cc ..at~.i, uohc a y v v v a ~ w v w a ~r v a o v v >.

~o o ar , ~ v . .

. . A 17 - _ s .. y d ~ ~. a~.~

N N ~ CO -O O !D ~
N t0 tp N ?

~0 ~D ~ O N JJ
~-i N G 4 r1 ~!1 ~D

f1 ~l1 ~

O m ~ w h -- L: ~C
o1 h w 0~

0t 0~
ID
O

O O ~ O O 4) C
O O
O O
O rr r1 a ~ Q ~
~' p eT a V Q
V e~
v ~

~ m .... ..
~ i w 7, D D ~-' a! y it E

o a a a ~ ~ - ~a a o d ~ (~ v w ~. m w wo . a =~
w a a -~ ~C m ~

iJ 4 Lj .
r ~ a~ ~ v o 8 ~.~ I
~ x ~C

a s vo G
E m ~m ~
J

_ ~
v v vv ..
v .
E

o a wa o ar as w a O
w ,. ... .,..) a a ., .., -.~
.., ro m ~~ ~
~ ~ ~
~

y y x x xx x x x x m o d w s d s SUBSTITUTE SHEET (RULE 26) WO 98/19253 PCT/US9?119362 E

m rr - _. . -C C _.

-m -i ...
-m C y ~
, m O U y a ~
.) C

~ '.
I

o y m ~ m ~
~

c .-~ a .~ j ...

O y o y -m c :J
~
E
c a m ~r ro ."~ ~ -.r j o a O .r w , '~ ~~
- g ~ ~ ar c ~ ~ ~, c .
ar y a ..

m .., row - O ~ w s~ E o ..
~

7 W . ~ . .
a 1 O o I
~ a -.

L ro odr _.~ .. ~ y I
O ~ t! - b U m ., w m ..

~

m_ "oar . 01 I _ d~
- a ~ ~ E ~ E

~ ~ ~ .1 .-a 41 m W o 01 _ ~ - . '' - "
- . ~ ~ ( ~ ~ . ~
E L -) a m ~
' 7 ~ ' v , -.~

m o .~ C .r >, , b o m t . I ~ a ..r .-~ o .-~ w m ., m .-~

t _ ~~ ~yU ~t ro L ~

CCd -. w O a O
i O
-~ x ~ ~ N a p~
E C -i ~ O O ~
"0 ro w I o o c -v -. m ro E y m m . m y ~ ro _., ~ ~ ,C
v .1 1 E .,.i C ~ 1r O m 3 .p, m a a s) -, r~ y C~ fr -1 b o ~ o .~ .o U
~a ~
c g . x a ro a~
a C ~ ro m :o .c t O U v a u C ,t t ~ 'i ' . O m E 6 ~ ~ o a.~ ~ a l ., C

~w u8y y ~
yy~ Orow~~~ a ~

~ .. EC S ~~s ~ ra os ..~

A ro .,a ..i m O w t ~ O U
y ai C C a,i ~ ~ a y-~ C 0 g.~-.
s a m ~ 0 t 'C O

v N 0 C C .-, m ..r L 01 1.
..) w m CI 1 t m p O y y O ~ O m G yr .i 8 m y ~ O y y O w .r m E o L

O , .i .~ ..r C 01 .-mr 41 Ir L .
r. w y .~ . ro ro m C ~
ro U

a~ .a,t C a y m O L ro . - . p . m p 4 ~, m U U alP ar _.) , 4 d ~ a~

ro x ai C C-a.., m.~ a u.. -,-,..,..~ a 4 a g yt 7, a o d m 6 ~ N C ,.., C d O O 4 C C
y .~ 'C

. .
..~ y C ~ -r .. ~
m m a , ..l ..i r m -i C U C 1 U O -a -~ C
. m .

C m m ~ a m ..a -.i 1 . m U y ~ .-i .-~ Q y 7 ~ l - ~
ro b C

. .i S 4 a~ ..r . .
U m 1 U C a~ a U , m . v ~ 01 m ~ a 1r U ..) w o C1 01 4 m w ..i 'C
o O

O . m E .
O m C w w C E .-) ~ r~ m ro -. ~ ~C a a _ y .., y .4 m y C .
o a C
'o m m ~ o a a ., ~ ., ~ a w ~, v o ~ o ~ ~ t R
m y C ~ E E .r 1r d) V 0 ~ C .~
o~ .r 4 L l.~ ~ 1 m y ~ L, 1r O it ..W 1 O .~ -.
fr ~ U 1r u L~ i ..
C . ~ .
dO

~ . W' ro ...~
p a >, 7 :J
.,.r O
a ., ~ C a L . a ~' m m 0 U , 4 C ~ 'L E x a~
E
~

a~ yr a! ai m O N O -a o ..
. 0r1 a~ 01 Ir 4 p .. m o GI r .
-~
"., ao a .a~ ~ L ae w a . 0 ~
.. . . o 0 6~w s. w ~ 0 o o ~4 ~io p ~ ' ~
e i p 0 L O
. y X t ~~~ o ~

. a , -~ s u .. a .. .~N~, al RO.-~-- W m~
,s , ~'l7 , 0 01 01- . a. , uw ro a0 roo a E 0 E
~o t m . 4 Ir Ir rr , m e~ . c w m o , .r ..~ C U a y ~ ~ ~
a m t o ~ ~ ~ ' ao C y ~
C u ~ ~
~ ao 4 ~o o ~ O C .. o ~ m>.u s a .
, G C
al O t y G. O I 1 I ~' ~ a v ov a t ro d O
v ~ m ..) .1 ...) . t 0 aC
x .
..., ...

y "~v m ~v B~v U.rrr.~m U aLt am 'Ot '~ C X C C C ~ ~ ~ ~ - [ . . . .
~ 'd a U E i .

v a o or o 0 0 -- .r .. ~ .
x a ~ ~
a y -r .~ -~ m m m m m m a m m ao m o a ..~ m m m m m a~ an m ~ o a oe m ~ m s 4 y ~- m r.r -1 ., .r ..) .., ..~ ..a C m y .i ..) .r .1 .r _. _. ..
s.. w ..a ..., .., .., ~) ..i .., ~,) C U U U U C C C C C C C C C C C
ro C C C C C C C C C C
C
C
t o d o o O O O O O O O Q O O 0 O
O
O

o m m m m_,..~.r,.,~_...~-,.r..~..,..,....,-,_.~. ..,.~.~_...,w..~
m 1 I I I I y ~ ..m.~ y y . ..r ,.~
1 y y ~ a~ a .~ ~ y .r ..r ,.~ .i ar y y y ~ V a U U U V U U U
U U U a U
U
a a -U
U
U
U
U
U
U

m 01 01 01 01 O 01 d C1 ~ al 01 or al QI GI m 01 al 01 N ~ 01 01 4t CI 01 01 m m m m m m o) m m m m m . m m m m m m m a m m m m a m m m m m m SUBSTITUTE SHEET (RULE 26) c ., a a o _ w y x w y t s s~
_ w ~p m o~
w io ~C ~ _ .~ G
of of t . .
r t ~
:. :r o ~
y !yt x y C f.: G
y y G C O ~ O
y ~ vw. y.~ .
x o ._ .. ~r a y a O ~ »
y . m a i. ..r ~ 4 t w ..., (., 4 ~ O 'C p ;) it ~ ~ O
_ _ _. ». _ . ~G d y y d .- C .~~v d1 O
O, , w .. . ' ', ~ ' ~p y 'J
.. 4r -. 'C~ .. ' .~ . » » » » .. . C ~ y p, ~. .r d .-. .. ..~ .-. .. _ E" ~',) w C d1 O
eat 9~ ... tr r~ mn ~ . . y .., d a ~o ~o~ ~ - w ar d o d ~ ~ v d~ a ., w ~ !! ~ ~ ~ ~ b y o 8 ~ ~ 8 8 ~' y w w E (' p1 ~ ~ ..a t fi ~ O ~ ~
y w .G ~ . II ..r .r ~1 ~'f Ir v W
°° ' a ~ o ?. ~ ~ ~~" a o, y ID m o of ro i~ iJ v .~ y a ~ ~.r w .~~ C o '~ ~ '~ .S ~r r~ ~ J G x ~ C O
-. y .r ~ ~ y .tC O CI ~-' x x - _ dxarm Lma.,~a 8 a ~,~c ~°~a'oea~'oo b d ~ w -- ... .. .. _. r. .. _ m m a a o m w m ~ m ~, ~ ~- >.
.., .., .~ .. ..) ,r ..a ..~ .. .~ y y p, b~Dbb~b~bbb y~ y~y~ ylyl m ~ ~ g ~ ~ ~ ~ ~ ~ ~ ~ m i a i o SUBSTITUTE SHEET (RULE 26) a C y c o a _ .

" O it y a p O

~

v ""

w ~ w w y ' w ac o v v ao dr ~

7 y a ~ .

~ ~ s ~ W O y ' ,, V
. a - ~ a v y 4 ~

O C G ~C 4 O ...

~ m y ~p v y 4 ~ '~ ~ ~ o . :
, r 4 , ~ 'O ~ w w ~ .

, ~ w ~) m m '~ a -- a a " ~ ;, , a v w ~ y ~' v O o "'' 0 it d a ..~ o c o '~ b d a r ...
o ~ v ' ~ a -a o, .., .) ..a y m a w "' r ..ir i y '.'Y -i v . a . .~ y w ~r y ~ ., ~ m ' v o m v ~ a .., C ~ -~ y C ~ ~ G ..~ c . ~ d v w .. v -x 1~ y a) _ b ..

C v I) d .. d ~ ~ y ~ . . . ~ r-~
. of C -~ ~ - 'C ~ ~ b C
~

. ai p . s , ~ "i ~
.

.'~1w y a ~ . dr ~ 4 ~ V C U a r r, m - ~ o er a , ' y i ~
y e ~ N .. .. p, ~ --~ v C
p .
R

0 pw . ~ ro 4 y ~ ~y C
8 ~ _ ~~ U

.~ . , y m - ..
, o '~ ~ '~ a ~ ~ r i I c c d .., c i ~ a a I ar _ _ a . a - ~
, o ~ 4 er y y '~ - i. x ~

O w w r.~ w .. " -~ v v ~o ro ' dP - r " 3 C
4 ~ i .-, x x .1 .1 O d c w ...)C v -) .r C L1 y . w it C v a al w O

v a a V ~ ;
O -r D w . .,.,a. a y I ; (-) t1 w 01 ~ .

D ~ H l n fi C
C ~

y ~ r- Ir : a ~ . .
i p i w . r p G ~ ~ :
. 1 ~
~
y . . a1 v m . o ... .. r ~
. a .
.) .

a v . o ~, y .-) .. ,..) _ o ~ . ' H ~ j ~ I P a w ~ w p .r . gy m ~ a 1 m ~ ( v ~
y ~ C

. p II
C ' '~ t 7 . , I 1 ..~ , >

~ '~ ~ ~ ~
p ~
.

4 .. ... y .. 01 ~ y ~ ~ CO
~ G~ ~ 01 ~ b ~ N b 01 i ~ y ~ O w fi fi ~ x .-y w ~ O ~ V

y . .. ~ y i ~ 01 4 o m . C
r N r ~ ap m m al y y ~i y v ..r .r w y .. GI v CI m d ~ y it > y w w > y v d ~
a1 a w ~
E

G L C x.c ycxy C q1 0 d m C 1 6 C O C 4 v c CC~~~~~E ~
~ m s ~
.

y C 7 -~ C -i C O C C ~ ~ 1 I 1 , ,,o l C C O ..err,.~,, ~ p) . a l l y 41 N p~ 3 ~

V
y y yl ~ ~ l I I ( y y y ..
y l I y y ...

y 3 3 3 -r -a v y 3 ..~ -i ...) a a m ~ ~ m a ~ c C C
a c n SUBSTITUTE SHEET (RULE 26) a a o m y ~ w a i~
' ~

a d ., 6 c ~

... V
V

V A

y ..a ~

G w.
G

a m .
E
' ~ w j s r ~
it y ~.

s ~
E
O

..
ar .-i o .., ..~ o ., o ~a eu e u y.

... ~ . ., v ~ - a i -.

y, . . y . w .. a v~

.. y AI
; C

ri ..
y G
.

w O
~ C
x ~
p i, ...y -r C
L
d ~
d it ~p v ..r y D
m r C
s ~..
..~
~
.r ,., .
a p, P 0 r:
:
~
a a =
~
o r 0 ;, ~.:
c ~~u ~
oar ou s ~'r~~
o -r '-' ~ ~
-~ s J
G
'~

.r o Z
m ~ ,m -' y -~
y ~
..
y -~r ar a C _ ..
~r '~
m mV

l ...
r.C y . ..
y r.
->I
4td 3 ...
O~ ~
m a ... m ae ~C
t ors ...
~
;
D~
-..~ .
c y -. ;
a ~.
v~
c ....
p ..) .
m o y . .
.r .~.
~ a G v a O
~
~
G
C

.-i .
-C

..., t '-' - - ~.
.r Z
~a ' .a -..i ..a ..
.C

~ L fr -pi .
p off to ;
L '-.G
'O
io V
pv .
.

~ o v d ; ... .
L
..
w v~
~

o s .,., ...

p a .i t y O G
G~ o dI
d ~r O
C.
~
~
C
.~

r ~ .. ..
~ ~ o~
. -~
C m ~ a 3 ...
o V
a ~
a o ~
l ~
R

. 01 e ~.) ar N
y ~
.x G
~y V
ro B
3~:
y dv ' w~ V C
y _ G
w .
r -~

.-, y -.1 or ar ..~ a ra.
t m ;
'c7 .-.
a, i,, s.
.
~
m -- .-. ~ a Q TJ Z

'0 t u~
'O

( ~
~

~ ~ y s~ a a ~
~.
a ;
' a 4 , ..
a ....
. ,,, o I
~
-~

_ ~ E
3 ~
V
, ~

.~ y .~
ar y a ~ -~ a ~ ~p r~
a ~ a .~ a O .
t .., a .
O

tt~ .. w o ~-- i t ~
a~ d a~ s o o v v u o~

) .
~ ., ~
.
y V

y ...) -r .r " .a t .a C w ~ w ...) w ..~ ~
I '~
C ' .~
t ., y "
., d L d .-r a of .r w d ..) ..~
Y

v CI ., ..) y ,..
a.i ...) t -~
d ~O
~ ~
d 'C
al o1 t ' m m y y t t X
~
L

p, .., C
o, o, a (.'' y y C~
d ~
C
.r v~
v~

~ ~ ; ~ ~~~o~o d L
_ ..,8 ,.......~-,d,...,.., ' t t C
d a d r v N
t d ~
a t ;
~
E
-i l ~

l e ~ >
l a ~ >
E e >
v ~
v >
d e y H
e y y y y rJ
a!

,.a e ~
..~
C

V 1 V f1 Ir GI

3 3 ; v 3 a.
; w ; w r SUBSTITUTE SHEET (RULE 26) a C

O

ro O

V 7 m W

d ~ . .r w 7 s. dr m E _ W N

W _ r. L

.., y b r . tE.. O
m _ O y ' 3 C

~ w ~ C

O

Z ,. E
,d ~ - ., ...

G C

w b J y O
C .

~ m a 6 o > m a _ o a o 3 d c -..
a ~ m o o 4.

m ' m m m ~ ~ ~~

a C ro ~

y~ E 01 m U .-. OG 0t w .
~

~ , b > r.
~ a E d n m 0 C
~

~ G ~ ~- 3 dr ~ m O

_ y y ? > ' - o1 3 . G
> y ~
w D m . m -. . ro a~ O

V y ~ > GI Ir ' ~ a1 E

y ..-. . v _ ,.., C ai ~ ~ d Z ,:, . fa ~
. .

y . _ - tt y a 3 ~ y - D O E- z sW ~ m Z
r ~. a o .-.a - . a ~ m ... m ar r 'r d -O .-r ~ - > 3 a ~ ~
D

d m . . .... La. . a. .
~ .-. Z .r 0) E"
~ y ~ ; r~ r y ~ ~, a r U -.-. ar ... ; r .v R
m 8 --- .. B 3 E- d V .-.
O Z

3 ~ m r.r - m . . . m ~
a cs. a m m - -- ~a.
t m O s 2 01 ~-' m ~ Z 41 E

d i , ~ . d ai ~ 3 of E tt a 3 Z al ' -~
Z Z -~ ~ ~ ...) d ... C
m m - ~. ao m w 3 y ao z oG o 3 . Z
; 3 - -~ ~ .
- 3 'v a r.. m d -- ..~ y d ar z a y a ' s - QI a1 Z y ~ ~ .a Z sr 'C
m .... Z ; m m 0 ~ CI
CI .-~ ~ ~ ' ro v - Z Z a - m (.
Z d y 8 -- >~~ ~ ~
yg C G~ 4 O
m ~ 0 i ~

C l~ um _ y . .
m9 r~. C~C_ r r . .
rsa ~ i8 .. T
C

m y m 'C - ts. .u GI d Z ~ ~ ~. y m cY m al 01 C Z > C
~ m ~ E
. ~

Ir ,-.- 01 C Y ~ o! d O, d .~ m ~ y 41 d .~ CG r >, v .-~
C ...~ 0G -i -- ~.. .... a~
d t: ..i y > r.. ...~ >, ai 01 > r.. -.. w >.

~ ': m ' ~ ~ ~ w ~ ~
3 ~ a E ~ ~ ~ C
w w ~ o G d E" ~ -~ ~ c m m ~ ~ . I ~.
~ ~ ~ ~

:. ~ ~ ,, ..a ~. d m d -- ..,-- ~-w E ~ m ~. > m E., r w z a $ a ~ m ~ ''~bafl ~~~~~~~~ ~~~~ ~~m ~m BB~~

'8 o~ ~e ~ ~ s~ 4 ro g y d ar 8 E
~ m ~ y d $ ~
> a w ' o ~ d ~ > ~ > d m x or E ~ o ~ m a ~ a s. w ~ s ~ v ' v a ~

a ~

Ir ~" ~ ~ s ~ ~
> X
ro t ! ~ ~ O
C ? U
.
~ ~ X

QI 1. 4 N 81 L U .C 01 41 1., L
01 L .C

dr w ~. er ~ dr w w a dr a a er w c1 a sr ~. dr dr v s. dr SUBSTITUTE SHEET (RULE 26) b b ,.) ., ~., C ~' ~ m U

G ~ ~ p .i .r o s r G w a r o '~ r V
w r a C O y C

w d b r d r a v o , ~i .. O 'O , ~

a .. _ _ a ~ ' ~ ..6~ .Or .-O~O ~
O

v "' _ a .~. ~ " ~ ", " ) : ~ m a z .r Z .. .. ~ a ~

.mC ~ ~ _oG r ~ 'O .~., ~ ~,C, .

4 ~ ~ ~ G C G ~.
m 2 ~ ~ -i ~ ~ m m E- d 2 a t "' _ >~ uw ~ cw -s ~z 3z d ~ 1 OG Z _ "" 1 'g ~ s a ~ -~ p p ~

d G; V v o C C ...
O . y p a m ~ ~ h s~avc az3 ~~ ~~ ~ y y w i ~ a~ a a e ~ w a a a ~
a v o Z V~ ai Z Z . ~ , , mr rr a ~
o a e ' ...

a a - " ~, y ( i . _ -, ~. " - ~ " a ~ -~ ~ g r .- ~ r ~ / 1 m ~ ~ W r "" 1 - a - ~, ~
_ i a ~ ~ ~ b ~_ w ~ . ~ a r m ~ o v b ~ r V r a a a d v a ~ r, t ', n a m v e~ ~' 4 >
~ ~' ' ' LzZ s~ ~zz '$~ g gy g 8 >
~ 6 g a.r ~o z~e~o a ua-- , ~ ~ ~
~... S

o a a t ae o r r a m o SUBSTITUTE SHEET (RULE 26) a O
C

L

a 0 C

>

~
x '' .r L

.. C m O
w ~ 0 3 a . d L w a v C U

L ~, ..~ d I

z v b C

o - w r - ~ m m w a C

ro ~ or m t t m E m 41 w E >

x " L ro ~ y d '~

y d~

C
C d b t . O

~ E y A y m A1 _. C

ro ".' .... . ~ ~ , ..., _ a~ - ~ o, b dr dr . . " C - ro C m . y y " y ~

~ y ~ ~ ~
m O ~

a y ~ ~ ~ a d m O O a - ' A m C _ -".' m 41 ~ ~ al OG N ,.,., d o d .~

_ ~ ro " . oC ~ m C a 3 ~

~ Z
.r Z y Z Z ~ t ~ 0 e 9 Z d -r a ~ c c~ "' ~' ~' ~ '.
3 Z m o ~ dr ~

_ m a . ~ - . N " ~C
i ~ Z

., r -- -_ . j a , dP
.

1 '' _ m d ~ ~ . m ' z 4- "
I c., ~ d ~ ~ ..
m . C ..- CI e-~ CI ' ~I ~
~ .. ~. Z '_' a ri m oc ~.. d o a -- ~ ..
c c re ~ - . -- -o ~

_ .. f - .~ . - . oG - a >, ..
z .r .. C . - r~ y m m r y _ a ~ ~
.r C v .~ O a ..
y aJ

t ~yyyr u.mr~y~ .~ o ~ . ~

a C v al C U ~ O N ' . y C ~
d ai aJ " y OG ..-. .-. a at "r ~ C rt C al ~
~

C 01 al _m al _ .
s G _ ~ ~ y-- ...>.e:7 o~ro--a -e O

~ a ~ m . m '~ E~ '-~ ~ ~
r m ~.. C Q~ ~ ~ ~ d ri ~ w y -r a '~OO~v~~m v . ~ d > C DC P
~

Cv a C C "' OC ~'' m p, ~ G.
. C ~ ~ ' 4 a O a E
~ N u f ~
._. u al ~
a) ~

_ _ _ ~ C i 1 U >, .r >) y _ C I a a L ~
_ C

a E 3 it .r s. rr a~ 1 t7 ~ ~. Er ~ ~ i. .i rr m m .) a ~ ro F O L
-~ O C ...~ C -~ / r a ~, ..., ~
G

w O . w w w p~ D~ a ~ ~ 'r 1 CI C -~ ~ ~ N ro y ~ w m ~p Z al ro a al o ~ II C ~C L d a1 L ro U ar ~ al O C ~ C~ m ae S~
fr 1 C al 9 / d ~

..r a y m y a ar a C w ~ a a 'o a d w > a ~7 ~C a L a t 6 w a ~ 8 a ~ a r~ al B >
>

s ro ~ ~ C C O 8 ro t C 7. ~
.~ ~ ~ O O 3 C A b a > ~ ro L 0 ~o ~ O a ~
O

O > L 4 al La V Lr ..) .,H a1 ...1 a) O~ tr w ~ ~ L 8 Lr a ~ ..) ~ ro y +
~ ~ a w a1 a w w N a~ a N ~ w al OG w a 01 w w al ac al ~c .Y

w m m w r o~ d d ~. d d >, ~ L ~
s L 4 ~ r a t t ~ +

d d . er > > y >, ro ro d ~ d d m ar s a a a i z a y > w > w ro > a. > > ~ gs x ,) s >
~

g ~ ~ g ~~ ~~

v v ~ ~ 1~ U U
~ 4 U
p y, 4 4 .~ .. .. .~ e i i I ~

SUBSTITUTE SHEET (RULE 26) w a y s.

w ..
y 'y w C

-i O

d~ 'O

y d ~, ~ a ~ w a ,., .. .r - b it ~, L .a W 1 4 al m . i.. y p .. ..

y m - a y -G v w U dP t ~

y v y ~ m y 4 4 a C m ~ y ~1 Z _ : a $ 4~ .3 ;
-a a w ~ ~

m a o o a -, ~ _ G C U 1r 1 a a a O t ~ ~ V 4 O
~

t a - o D y y V .. .. V o~
a~

..
cr a ~ a a~ . >

~

~ ~ ::
d v w o~ o... a -> ~ ~ v~'~ ~ ac ~ sr ~ ~

. ~ r y y . A p ~, .
a s 'r U C ~
a d a o as -i P
~
~

dP ~ - r . b b l f ~ 0 ~ C 2 a y y 4 ~ .
a . p b a y V A
y V ~ ...
y a - ~ O t m x y ~ . y t a p1 4 y x y y .

-eZ U--47Z u7i a aX p~ x uW

.. v ~ ~ V y ~ ~ r:
~. y C) y _ ... ~ _ ao .
t r y -r y a~
y t a a ~ J Ir 1r a -y r _.G La F
~ r 1 t_ Ir ~C

: ' a ~ a~ ~ o ~ v ~ s z ~ o L ~ ~ ~
~ ~ y ~

. a 0 y r w a -r v o z -- ~
~- > ~ w v a w ~ o w >e ~ a~ y ~- y ~ o ~ w y ~
w er .. a a a O~ R t a y 8 y y y a y t.. ~o a y w t fr O ~ y ., w ~c ~c ~ a b ~ ~
x a a ~o a a m ~ ~ C a y I c o v a a ~- a ~ o ; y ; a . a a b 4 w = y ~ w ~ u y .., w v '~ ~ ~
,-- w y y ~
O

o w ~ . ~
o x ac _ ttooo z ooz O~ -~ ~O~zs~ ~
-w ~ ~ y ~ ~ a a y -- ~ y y O
p O
~
o a a a v a ~ w w m C or ~
ae ~. ~- --a v +
a ~
t ~0 v O a O i O O
4 m m y a +
a w w w~ wi as iy .se ac x .~c ,se .ac U U U

U U
U

SUBSTITUTE SHEET (RULE 26) a _ O

C , G

O

_ ~

L m ~ ~!
>
m 7 m ., .
of ..~
O

U
O
y y c . o a ro m ro fl o ~ m a1 t a m w y GC y1 ~
rJ to G, .

9 ~ O m m m ~ t v~ p, s.1 W
a it ~, ~r, it L
O

t a %a a ro O
~G

a ~ o.
w y m b .7 ~
~ U ~, O~
~

it C 1 C
O 41 m it a C "' -a ~ O
w C C
O t~

a -a a r~ .r t C7 ?v .r A .~
m U W ~ rl 7 ~ m .-1 m ~., ...~ .-r p p N ro ~

r d . l D~y.
r ,, u O

O a C ~

m n .1 y D
. ~
O
C
0r _ O C 3 ~

m y ~ O i a d w ~ O

C m N a1 C
-a ~
. b O
~

t >
a a ~

ro x ~ >
>
O
~
>'v a~ a1 - y r.i Lr rr - - w t C
b C

b ~ ~ ro b ' ~

C CIp~ ~
~
( 4 d1 O ~ r Wa >~ v ~ >, >~
W
p ~

y y ~ m .
O
O
m ~
O

~ w - C d dPm dr i.
C -i m 7S m y ~

d " .,., 4 GI . d 0 .r .-~
.
t QI

do - ~ 7.. ... > ,u a.~ r~ ,C
t .
y m ~ . g O ~' x >, n - r ~.. .-, .-~ ~ ) dr o . d .-) ~
w .-b .... . . .~ , m ~ .~ E pv ..s b w ... w m V s. O
E 't7 y m O . .....,.. .~ w H C a O ~ - ~
~
C
C
b T7 ~ ~ t m ~ ~ y ~
y w t w ro ip O x C ~. p . .. p ~..
~ sr . ii j tr m m o1 O

~ m O m. m 0 m GI C o1 - >, ~ O r~ 'C Z "~.. ~ .-- 0) O y ..-mr~m ~ " d .-v .
~ s. ~ 3 y .ar -->
>

y t a~ are O ro y cG
r~ O m ro .. ~
... m i ~C ~e m --.~~~ u..az--a x a~L a _ y m m m y a w ti ~ & ~ _a~ ... y ~- . ~ .. a aJ m GI . y m ~ ~ ..i Q m t -r ~ 'C a) ro t w m v ro ao ..~ C
O ~

) ~ ~a ar ro rod ~ ~ .u y o ~ ro ,-. ~ m w ~ y ' . ~ v~
x ~ ~ - o a~

. a m v s1 v - a a m w o o. ~ O p, . m m ~ a -- m ro ~. ro .. . o -- a m H L _ .. ~ $
~) c r ~

. o ro y y ~y w O ~ y m m m - w a o ~ ~- O d ro .
y ~ ro ~ .
a y a Wo a1 ac lr w 1aa W. L y) 1r O 4 ~ w i1 s1 y y) a d i!

m a .r .rd O x W 0 GI m .., 4 O C1 N ~ ae ~ d ~
al w - ~ U ~
~ t .~C 7wr ~ yb I da~W ~~L'~ C
4 U 1 a r U ~ p~ >
O ~ 01 ( O
l~

w ~ m7 O O ro N C~ -.
w C

U ~ p roa w + ~ w r.~ ~ .., ~t a + w ~

w m r ~ a t r GI a d U ...) ..~ U U U O~ ~ r ~
O~

SUBSTITUTE SHEET (RULE 26) a m N

C C

' d O

a U

L

~ '~

, ~"

b w C
a r ,u ,-O C .a U

V .
b b 4 z ~' ro .., ' a s~
'o b z v a o . 0 a~ w ~
~ >

A
~-: o '~ a:
o ~

.
y C
fi r .- .
01 . .

a , ~

.r C C d1 dp N ' C

V ~ .", ~
w V 4 _ ,.) , _ d y ~ p p C ~ p .~ ..
H a . ... ~
-,.
r C
.-A A w CI a ~ C1 ...
..i ~ ... ..~ ~1 a .-~ A
...

w C~ A f .
~ ..
~

V O m Q .~., ~
8 - V ,.~, m y .~ '~ O
.-i m ,-A

w ~ ~
~ m ~
C C m O
.u 01 dP O E A
3 ~ R - GI E A
O ~ o c -, -. ,G p ., - A ~
ar ~
. $
o V . ., . ~' .

-1 E C w ~ o A
Z E 7, ?. ~
y er 0t I a E
w a ~ E E
~ ~1 P
E
~

_ A
P d ~ ~, O 0~
H
O

O ~ ~ ~ ~ G ~ -i~ 4 a ~ x a a E
~ . O
.) y .

..~ -y .,i OG ~ ' .-r .
p i . C
p ~
~

H3 ~m~. .C 0 ~
O ~a C
"~ ~
C
~

D .aCb ,) p, - C, ..
i p' O ~
.
..
r .

x ~ C _ _ i a~ : ~ O, _ ~
z C ~ 17 a a : b' o d ~ ~
i ~

I -_ . a. .
or ...~ . r r a p a y d m u W al .. ~ ..' C
t~ of ~ ~ p ... ~ ,~ ~
m ~% ... Wp d ~
fx w ~ 5~
, m ~
.

a .-) w G _~ er C a ~.
O .~ t~ I1 a .., ..r _CG ev ~ .
o C O ..
3 y -r ts. a ~ C w y ~
N .-i a v ~ m ta ~
~ w ~
Z a C
p y O r ~
O d o 0 . ' 0 L u n ar O
A
O
O
~
~
C
t "

V , O ~ r G a w o O C
-r Cr w d ~., w O
,u w I~
..i ro o w ~
w w or w ... y .- .. 'G 4 v y, r. p .r y v as a ,.. y v ar 4 " b ar n. a~ ..~
ar ~p ~ ~ ~ L'i." 7r A
p C C C o C ~
4' ~ G C y a o ..a A w c d ~ ~ ..a ~ .r m ,u G ar,..,., o ~ ~~ 'r ..~..~...so .~ '~~ y~ ~'R
ey uy~
y~

. rr . c ~ ~ .~ ~
a~ .-r C ..) . .r r.
..i y 'r ..i ..i C ..) ~ ~) s. .~ .~ .r _ A .r ~ ..i ..i ,.r .,.~

A .r d w s u. !
a 3 CI 41 Lr m A !r o ~
...) fa o A o o N

d A 7 L. ai ..~ 3 y a .~ a7 3 3 rW
~ ~ r w 3 ,u ip ~
~
s .u 7i 3 ~ -~ ...~ ..) .a ~i ..i ..r ...) 7i ..i .r .r w 7 ~ Ir L 4 fr L, L
.-1 !r !.i ~ Ia Li L f.a o www e.sa ss a ssss ss s SUBSTITUTE SHEET (RULE 26) ..

ro a L

d o n1 E R

V w ~

P O O -C C C

>) ~ ro .

~' ro CI V
G ~

- C E ~

w ~ 0 ~, o A ro d a C ~ ~

t f U 3 . r o m y A

er Z

C9 s. ~, y ...
C

L ro O p 4, ii p GG
tr N
~r m w - a t 3 a i.
a D
v o1 ..a a m m a .-~
C

d ~ ~ ~
~
r P C O 4 ..~ .) R a .
~

C ~; ~ . a ro V .
w C
V

C w m 4 U
-i .

C m ~ A
w ~

d ~! . .- ~ O
m ~
-~.
C
m t ... p L
a 4 ~ ~ y >
~
~

w m ~, d w ~ C G -~, L .r 1, ~ L N QI ~ ro ..1 01 ; ~
m ~
L ~
~

t~. 'r R R Cw .~ r~.,~ ' E
m C Cnro . 3 3 ~ d Er O 61 V C rr Ip r-1 lT -~ V .~ Ir ~ L
.~

C ~ 3 m V 3 a .. ~ ~i ~ - 41 C~ s m m a % tT .~
it ro U
.- d O ~. 7 p C N .. p 'C d C ~
d t m d G ; G. a i~ .i p p a .,. +
C .., ~
.r a ty a .~ a 1 m w C l1 ...r .., ro ~
p V
~
G
~
O

y p a ~ a G E C
V ; m ~
.
r a N . p a ~ E - ~- 11 ~i 0 ~.
d v~
O

91 d V O d~ .-. ro C
0 a) t C
C
C

v a a ~ _ .-, a a ~.... p p ~ x t m a ..i ., GI m m ., Ir d p, .r O .. i. - ro d s. . N a rr -r 'C m p E
dP
i.
a O~
dI
C

C ~ x ri m ~ 04 " w L 3 "' ""~
~ ' ~
t .~ - of . "~ _ ,.
. .- . ,~ !
. r a 'O V ~ 'C .r .-r - : C~ d ro 3 C . C1 9 ; 41 ro V
C . C '0 L 3 r., 01 -y ---ro C
C~

I - .r a V V 0 ..~ 4 . ..
.-mp I ..i t m G~ 0 ~
..i .
.
C

w V '0 (,1' .. ro a O -C C s. ta. ~r C 3 w C
..

~ .. Ct C 9 d 'C - I > ~ C
al .~ 01 m ~ O .G 91 .~ 3 lT
m ~~ ~ ~ ~v z I
~~

p w ~e C ~ j j j ~ Fe a m ~ - .r (-.v ,~,w ~ . .~ (~ m-~-.
C ~ N . p. . $ .. E.. .., y ..r ~mp I 17 ....

_ ~ U ar I I -~ ( .-. 3 ro ~ m m C ra m ~
O C E m C

p I D 1 3 3 . ' v .a o1 ~
p .-m G1 y -a C -' ~ C
~ C m .rc E
-r m v N

y . C E C -v G ~ _ C-~_ a w a H C G ~ ~ _ 1 _ C 4 m 0 b ~p _ w ~ m a% ' $ Z ' d w . ~ ~ dr . 0 _ ~ ~ p m . 3 C ~ _ ~ a O m ~ dP ar ~ $ ~ $ C
.r y m G
~ ~ m ~
~

y 'o I'vuu 'vaa 1 a - ) dcyorroro a - ao -r crdd 3m G m ~ u G
~
G

d . .- ~ ~ .: C ~ N ~
.~ ~ ~ 3 ~ ~ ~
~ ..
~
1.
~
~C

-.
.~

ar al c ar .~ m d m dr o) +~ d ar m ~ 3 d L - d m 3 W 'C a a ar a a .~ t a ,~ a m a a a a a ~r a a a ;

..., .a ., ; .,i -i .,r ..r ...) ..~ .a ..r -i .., .-r .r 4 Ia Ir 1.~ 1. it N !r La !r Ir Ir 1. 1a Ir 3 3 3 dP 3 3 3 3 3 3 3 SUBSTITUTE SHEET (RULE 26) WO 98!19253 PCT/US97/19362 a a C

a~

C

t.

re v L

~c ., ,.

-r a r. a w y -. O

w C ~

s oG

_ y 4 v 3 C s ~r ~ r .p y .

~

O -C

ri w ar ~.

..) . w on w a>
oo ..., p. . . ; ... a ~
t7 ai ..Ca j~ . ~ a ., " -~ .ii o - - .~ it w a~

~ ~ ~ ~'io e E o . v . v a --. w C ... - . ai ... . . m 4 ... .
~e w ,., O _ a au _ _ -- a _ r s.

..,w ?. it . o~ s o~ C
. 3 , .~r v 0 .u . o . w -~ ~ . .., w ..
.

E C - O C ... y y . p ... y E ~- . ~ .r ...

rJ -r oG C O a~ G a ~. .,H C
.a a~ 41 a~ ... ai of .
ai y .s)m . ~e -.."r_..., ..owy~we~a mviC

.. . rl y .. aJ y w 1r w ,rJ U w ,~!pv .p Ir A i! a y ~
~

. .-~ ~ ~ 3 C a w y 8 B aC ~
C C ~ a a w a A r-i d0 3 v aOCa.wuh.--~ ~amp .r ~p a .-. -. a C a m -~ ~ C ~-3 . e .~ ~ ... .i w v v~ ... ... _ o .r ar a --~ it C r.. w y amr ~
. , ~e CI C -r '" '~ ~ A a ..r lr a~ -- Ir m ~C -- . y it C C
~

y .., w W ar ~. a C .~ ~ C ~ C ~
r~ . v -.. . C ~ r O
ta. . 4 ..

-r ~p m C C - w w v a ro w m w .-r .a -- 0 w v a o w ~
Z

f.._ 3 1 a y a a ar ... o a y w C ..7 ~ w o . w a~ o~ 4 D
3 ~.a ~ ~ . C G 1 a ~r p C ~ C
3 -a d - cs C O O ~
ar a ri o y y _ ar v ~ ' o ~ ac ae m w ro o ae y -~ E > > W w w W Ir d ~e o aJ m O~ a w a) do w w Ir L
~ ..a ~

~ ~ m a ~ ~ v o o b ~ w a ~
~ L ~ 6 ~ ~

s ~ + 3 ~ ~ m a a i y .u y ac 3 v v B ~c 3 .sc O oG ae x B .se D~ ..r ..i L Ir Ir L. Ir G~ G " 4 b a 3 3 6 B

SUBSTITUTE SHEET (RULE 25) o d L
W
E' ~ V
m a -.
m i: w a ~
v~ m o m ~~ m b C d y ~ C m ..~~ y m U
~ O ~ m G C
_ C L
A O do .~ "; y ~. a m .C w w w ro 6 m y y ~ dP ~ di ~ 1~. y ,p m y ., ., ~ ., dP dr p y ~ m V Z , - to ... _' t1 m o a , i ~ ' a ''' a ~ ar d~
ma a.. ,v ..i y ro . d a Cm1 .a D ~ 1 , .7 1p.
y . p, ,.e., B y C 3 Imr 3 ' Z ' Z r n. .. .~
a~ .7 ~ ~ m 2 m O r7 » ~ O d . .7 7 3 U O ~ .-~
3 . ..i ~ ~ ~~ ~-: ~ ~ ° m o _~u° za~ v o . o c~z ' ~ C ~ ~ ( w 4 00 0 x m ~ a3l ~ .7 ..O.i s ~ .Or ; ..~
a ~ a ~ O Z O Z .4 m ~ y o m _ y ~ dr 4 to U .a v s 7 m m Z 't7 m d ~ d ~ ~ m ~ m O m O .--..o m , r-~ y C O
y m ~n m ~ ~ x v~ x d d c a m ~ .o .., z a~ . ~ yl . ~ ~ Z i~ ,..~~ ~ m ~ m v~ w .r ~ ~ 1 Z y., ' . ~ ~ ~ O
as m m a a .a- a o a y o a a~
-1 _y~ye e~o au~.o m3 romL.. ..
3 . ~ m s a r~. > > ro a o o > ~ o ~. o s~ o a v ~
. ... ~ . o m ~ . .~ .c a m a w z , .~ ..a N p N ~ ~. a, rl Q', P ro . y ... .~ v v . N ro p r-1 a ri ~ .-1 ri (;
3 0 3 orb » .i y .-i ii . .fir > a -- ~ ..- m f.r m .~ 3 > a V o a o > 'C
.~ o m -- ~ ~o ~. .~ ~. ~ m ~. a m m 'v ~ o s. ro c 3 y ..y~ d on ai ~ a G ~O m ~I ~ ~I , 8 ~I d 2 ~ d E D o ~vp O Z _w l) U ~. ~ .r p (..) w ..) 4 n v ~ y m ~ ~ ai ro + a .~ ~ a .'~e~ 6 .~ 3 x ; ~ o a ~ ~ o > o °' o a n ~ C a m a w ~ a ~- ~- w aC ro x ro m ~- ro N v ~- Cr 8 a C o 0 0 a j! .-~ o 'O it y ro 0 p a a t ~ 6 B Z w 6 .7 I a ~ of ~
m v 3 4 m ro w ae ~ ~ ~ w w p 1 X ~ ~ ~ a 4 .~c ~r ~a p O ~ y 3 y ~ 1 1 1 1 ~
4 01 0 la 4 7 l.. L o O y y o ~i~..j~..~ aao v~~~-~~~um m ~3~E~ ~~ ~4 m 3 3 3 m > > a B o ~~
y y O
..~ w w o ° ° .a a 3 3 6 8 dUr a a O °
a d, SUBSTITUTE SHEET (RULE 26) y a v w - . w s ;, a v o b w ...

w a .-. C , O

.., s a . m p .., - ro .., x m a o O

m .., O . y .r ro Z ~

>

J ~

J p y 0 s -' o .r .- .r O a - w aJ a~ ro . w 3 > o O

a a s~ 3 ~ y a m e s y O

-. V Z C

P . d 3 i y L W r , w ..

a A ~ ~

m C E
~ a v ., ro v 3 a .
- o v .. a d cc O a ~ ~.
v .. .., ..r .. ~ _ w . O v O
oG --, ~ v ro y ~ . y yW. ~ ~. G G .r ..r . C V

O G a ~ J ~ r1 O O O O
~. .-. ro s J

i G i m ~ z Z y y ~
m I . y C ~
d ' O
C

S ~i x ~ ax ~ m ~ " sz ~ .

~ y v . , E r~ ~p .... v v >, m . .a ~ . o w o .. ~. - . ~ !r C1 p~ ..a L. ro rr 2 ~r G
O

dr .., dr o w (.) 1) .-v x 6 . . ~r .r .. y a1 O a~ o O v ~O
.a - y er O

C v a; .~ a m yr .r ~.
~ . v v U

s s p 1 4 O v y 1.)G .i O
o) ... .... v ~

.a v .7 ~ .7 v ro a o: v -~ ro 3 a y m > ~ y -w -., -. rr +
a E. p,, ii d o - z ~ a L . - o a ~O >. - v v o z ro x v o L, G 1. . ro t1 s fr ai ro a ai a.i li 1f E 1r r! C -E

E a s d s E G ro , a a a a L ro . 0C

v .a w v ..7 i v E s. ~ v a~ .., ~ C 4 ai E- y ro ...
-E Z O ~ Z y ~. ~ = .-) V .-r ~ ro a O v J
s Z IT ~r a !r J . ..~ 1 a E- ai C !r a , s .7 a s~s a oc w ~..ro v a , Z ..a t7v s . a y ~- J . s~ I
y v ~ w v ro .
a j f $ ~ os . a i.yx w- m~>
o a y a i - .-. v ro ..a~: v +
y ro a -- ~
i _a a ~ ~ s a a ~ oG j ~ E" y $ a a m e a y ~ i y a y .. .. a ~ a a -, a v . , s -- y -a -- s -- ~- . ~ v .
z s 1 s j .... m v m oc y w --~. a O r. ~. y o~ -- - a 1 ~ a -.
a x ro ..c v ~ o y ..a ~

.tt 1 4 ..a a 1~ a -- -- ~- v a ..
J a 1~ ~- t 0 4 !r IC 4 a aJ z a w O -- ro ro ~- y y y a v 1-.
~- O w y s ro .se t- v -~
t ro m w L v y ~ a a 1r a E L a w v w o m 6 ~ -- ~ .-~
v ~ ..

p 0 O 0 O d . , t 4 41 r. d E ~1 .1C
n r .. al .~~ .y) ..~ V -~
L. Q ,C v J 0 ~ x a o o v~ o ~ w .- ~. .c ~
o o a v -- ~o >
o >

a U ~ ~ w w w i w u ~ w 'o 0 V ~
' v ~ ~ ~
=~

a ~ ~ ~ er s ~
a SUBSTITUTE SHEET (RULE 26) L

41 al d C

al U
d c v a G

it a m ~., ~ a y a rl O ~ ~1 ~ ...1 ~ , w ~ ~
D t v ~ L ~ c O

a 3 a ~ 3 d A -~ .r 4 ~ y ~
w d1 CI

.r ~ v G ~
", p Z v w .
~
01 ~ C~ ~
O

a w t a m a a : o ~ a ~ L ~ w ~ L ~ m a .r y rJ
c d r.l C
t O w c li A a tp , c ai 7~.ZOdm y b.
u ..., ova . ~ .
~ G ~, .~
~
~
~

" Nairrw R O J
~ -V d~ O ~
' ww ~ o 0 0 ~ a o x ~ " "...
C o ~ a ~ w 0 o v A ..r ar .r .r d y L1 - O ~

C & ~ w ~ ~ p a a a > w o d ~

w . d a '~
~ m a A

dr m y x E 'O O d b w ~ O ...
fi O ~, ~p 3 m J L . V
r d1 D y 'O 3 V L
a ae -. w C w d~ b . _ m ~ 3 _ O y C~

O a ~ d' dr ~C
. a D
~ a a ai .ai ..~ ay ; a 8 a ~ di o ~: s.
~ O

.a .a ai m w - ..
., w ai m ~ ~ -.
'17 ' 3 ~.
s, rtl ~r o O ~o a~ ~ V
.a aG d o a a C ~ E
d 3 = ~~

- ' ~.
s o m ~ w ~ ~ a ~

e ~Z 3 c .. 3 ~
~ ' c ~ W ~ ~

a c 3 ~
3 ~ .

. ,p . a '~ 1. ..~ ~ ~
y ~ t . .. m 6 .~
t a .

o r.l .r CI ~ ~ ( _ ~ a w J
~~~ A
.a r O04 C r , m ~ ..7JJ t~ d pyz ~
t CC a.
v .-~
a y dr ~o U 3 3 ~ d a w 1 O 3 % y ~ y O Z ~ d ~ m % O ~ C L d CG
Z O a .~ c Z ..
~

m w OG ~ p 'C . w e1 d1 -a .~
a) ~ t ~ 3 r h 1 e) . O
V
. 1.
.r p U
N
.C

C a i.. w p) w V ~ D.
w .r d .-1 4 O
!r w . b Z

.~ O O ~ _ ~ .-ar O ~ d r1 ~! ) U
~ j O

r, O a ~ ' o .-r c , C J O , el m .-a m ~ v V
, ~ O A
(p c y ~
1, O
~

O ~3 w O
0 3t3 ~V
> 3 % ~
V ~
U

~ V (_ ~ p C
0 '-' O
G -~ _ , .... L 3 a w O, % .. % a! J .~
~

w _ O V J
C~ 7 i !~ S w GI % ~" O
~1 ~ % v a 'w' V

~~~ ...a L ~ d mww ...~I %
' "
L ~
x . . . w v ~ a ' a .a~..~: w : w L w -r '' o ' ~
m w o d o a _. ., b ~ ; . _ c. a , ~
, I
, >

_ y. 0o~~EwV~O ?~""
a~>~ > tv >001 o..r~
' 01 ~ ..7 C7 _ .' 7 ' ' o ol ~ J ~
a U
O p v r _ ' ~
a r. or w r .. ~
v .r V
. -W ~.
- t c ., .. r L
d 4 C
V
~
~

_ d L 'Ow~O'CO'O i'C ~ 00 .
~~L d a V~ " "' U
' C m C O w Iy, O O 3 '0 7 u .-i i u .-, O
-r , ( G. O V 'C Z l y p ~ Oc b O al c " 7 y N ~ O
,~ 7 d 8 ~ O
l N ~
~
v t m O .r ..) C O.-a LLrra'pd'CG.~O.O'CJvaOLOCO~ ~d 8 mr m r it.~O6CW~~....id~ ~oooa'va'oo.La oc a~o~da ~
I

.~V aOdO7va a l (~ V
J 1 > a c ~r A ~0 ~ m ~0 N 3 iC U

Ir ( y G. c ~ ~ y 3 a ~ ~
m b --~

~ v t0 3 ~
n1 rr A
a w ; ar dr 3 m dr dr SU6STITUTE SHEET (RULE 26) x s a _ p a $

x O

a E w $

. .,-m -o o x ~ .:

a , .., . y " ....rr "
z e ~

~ m . 01 ~ m .. fr ar C C

~ 0 o ~ y ., .. ..~ O

_ .., w~ w U

3 ( "'' G ~ ~ d v v ,., G .. w .-~ z o a o ._~m o -ou .,p. . .. m w w .
'"~

v y .. O C X
e r Q .

a w ~
. n O O
G d x a w ~ , m y O

~ i ~ w 3 w m ~

... a O ~ m w 4 w N O 3 3 a G
G

x n ( , .~
~

.. .r m N 3 " ~ 0 ' X O 0G
~. ~
.~ Q
' ~ ~ a ~
w y, .,., ... ~ ,, . . a r... - ,~ , ~ ~ a ...,~c ..w ._ v o$ ~ c x ai. c ..., w ~ ., .- -- o -.
_ ..~ w ~.
o ~.
.., .", o, . . . ..i ~ ~
w a w a~ w y o w G ~ ~
C a C
~
~

v o ai.~_ H " a ~ C ~ E
pl as O
a ~O
O

ae ae a ~ 01 Y ~ a r o 8 a b y d ~ d ~ itr .r .r w i., 4 .r ~C a v o ~
O ~ ~ a v cr ~
(v a ~ ar v .,a o a ~ x "' E Pv ' O
~ O O

.r 3 O y w ~ m w w tT
x i G 3 ..

SUBSTITUTE SHEET (RULE 26) -14. .~
d b a b d a w y m -~ a o d a a o _ C

4 dl O

y ~ R
~

.

O

~ G
w .-. U b y ~ v v a a c d ~
L

L G ?~
O

. a m O
.r a a x a~

m a v .. p, m a ii w 5 m ~ D d _. A ~ a m ~
..a y w air O a .O i . .u O O ~
. p C

. 2 'C1 b . ~. io O
w ai ~
.. ..
y p x - a ~ ~
m v > 1r v ~ a x a ~ ~ ( ~ m Q ~ > .
: $
~; ~
~
~
w . . .
m . v .. ~ v a . y ~ ~ . ro y E ~ o~
6 v~ ~
~ U -~ >
..~ C
G
~e ... v x v .1 v ~o m -a .
x .a a a a~
1 ~ > ro C ..) X i ~p . C . >
'C 't7 ao C 3 .-. .a O ~
3 Cs7 ... C
y C
...) O
x v I Cf ~ 5C
v y v a1 m ~, d _7C
w w Z .-, OvG ~ ~ a Z m X ~ U v l7 ~ d~
~t ~

ro ~ ii rC -' 'Cl Gv. ~ .i y OG E Z
x v v v y ar x ..., o" ~: ai ~ m. ~) o ~. x ar x x o y -.
x ".. p I V Cb s~ C "
" ' I ( . V Q .G > .-.
V U
,.) v .,..

3 ~ ~ -- >, v w ' ~ >, v -.
'O v ~ C
v ~

v G r C > ...) W > b a Z v Y .,i .r a~
~ " C Y m ~ II
O E
ai r a~ v 0 ~
~ b ~

~ _ - w _ 4 ~

w ~ b G w 1 w 4 m ~ ~ b ~ b ~

c x w ~ L -a a w ~ ~
t~ ~ ~ -v ~

d ~ w x y x . . O ~ r.
m b : ~ w. a x O a x t7 a m Z w w v ~' p d w ~
y .. C ~ ~ ...
~-_. o a a x s~
A

m m ~ o c ,.m r SUBSTITUTE SHEET (RULE 26) C

O

U

L.

L

O

w O
t a > ~ O
~
y >
~

C ~ 3 R
t d >
~
t y -, w x a ..

E ~ w ~

a ~ a a .
p , o o , ..~

nt >
~
a m E y ~o er a o a '~
~e C y wv o , , ~

He C
. ..ao~~ b :a ~ ~ ; y , C
! ~
a ~

o ..Qy b t ~
a .
C
a -.a b _ >a.a;

y '~~>~~b m i ~A s .
.i ~ Z a m C
y x a ~ d E i 8 !
4 ..1 m% x 4 o .. .
y ., ' o "' ~

c o , >, d ! , ) 3 , y a c a y' ' c a nt ~

~ 8 c j a ~
~
~
.Or s . 1..
m 'o 0 o ~
a ~ O
"' ~
fl ~
a '~

. al ~ Lz~~ c ~~;.

8 a~~>~~w ~ ~ '' b N .'" ! > :.
x a a i c c z t ~
c ~
-~ ! > , o x A

_ c a !
m a ~ m > .;
..i ~ -v t x roe.m .. o a p~
o .a .. 3 v~ ~ wr.
. v -.
..~p..~.~..

m x . w.. ~ ~ ~ b O
m a >. C
c m =
f m ~ i tr >
b >

ms w 1 ~ ! V
a b ~

~

,. = A ~ w " .r s y E ! .-~
...1 ~
Ia .a a1 .,.r ~

rr .. w ~ ~
'~ >
V L
w A O L
! ~ ~ ~
~ y a ~ t~1 w O ~
~ >
w ~ ,,, O a ..r ai t ~

.r r ~ ~ y~~t 47.
>= s t t d~ i J ~
~: r lr rr '-' "' 9 1, ! b C a "' Z ~
O ~
'-' ~
O
.v o c > -~ > ~

~ j .r .
~ ~ .
~ r , r.

$ r o r a ... ~ a ~
r n ~

_ .
~~ ~ ~ , ' oa(~~ ar l y u~

.. o a l a r a p x a w dr x x ( w $
-~

~ 4 8 U
~

_ y ~ s w a ~
er dr dr dr er a er dr y SUBSTITUTE SHEET (RULE 26) .. o w o w t a ~c tp 1p L

m s,., a V
W

m .. al a .
~ a t .. .

.., n a a _ m d ~ a -Cr ' ~ 3 '' ~ a ~

o, ~0 a m ~.m~C ' "- mBS

~ C C

-a ~ 'G m d Z

~ - ~'~ > >
m a m ~ 0 ~ ~ x X
~
d .a . . m m A r 'v w .. .. m ~ oa a C m .-, > C 6 7 ~ ~ Z ''' .n ~0 C
O

,..a~p a O O m rl W 1r w 7 w w a a a 1 ~ .
i o r r r > E
l a~ m D. V .r O .r .1 ~ a a ~ A d1 ~.C
C
.
w .-i yC

_ 8 or a ~ w ..a ~ o A
0 a - +
>

A 4 3 w m O
tr >) U
~ ~
~
m a b 6 ~ ~ ~ O O o. .
' R ..
~

~ O y w '~ ~ L~ fi A !!
~ ~

4 ~ V ' u '~ B
V ar O

. O 0 V 01 . ~
r .
C
t ~ G ~ o X ~
C C
a O U r O . u A
>

a 3 en dr o m m b - ..a ;
~

d w a a G 3 >. O
d ~

$ ..,. a~ 41dl ~ ~ ~ 01 p . a o a -. o v~a - r r ~ v >. m A
a r a ~ C ~ ; o~ot ~ e' a o w . ( . .r a a O a U
,~ . ..r O
. .r a . o m - A -r ..r ~ ~
D E O ... E ., a G
G.
.i 7 nT .i m .~ > C C .-~ m ~0 '~ .
m C

a m w c ~ -. a 7 ~ O ~ E
; x ; -. x; B
to 0 ,, .. ~ o a ~ m d ~.. . r) 0 m m s x ~o - E 8 ar C
.r a Z -r a m ~o R ro ~a. ~
.-~
Er m O., ~ ~ . ax- d x~._~.p as ~ ..- ..~v ,m~-~ a .a V m o m $ > E. ~. E. - >. m o ' m ~ a .) ~ ~ m w ' ~ E a o C
ro .w ip C1 G ~ D. d . - . ... o~ o ua m m 7 o ro o a ~ . a m o ~ o .r ~: -. m 6 mw - s -~ m -. .~tl~o v~
~. ro -, x c..,~o ar .~
x mx o ~ a ~a a a ~ m . w _oG
..,A ~ ~ ~ O
a A w _0 r 3 ~ ~ ~ m .~-~~ e1 iC fC ~ C~ a 7 ~ 0x0 y V m ~ C
7 1 r 1 .,er P~ X

W E ~ e ~ d ~ C
~ 0 ~' o t R ~. ., A
B .
, ~ > yy ~ w a~Ia~srn ~ v~ m C
a a d o~~
~ aer . V C -i a A >, D
~ ~ w .r 1 m iJ ~ ~ n v ~p a 7 ~ ar ~
E
--i .. a a ... ~ v ~r w ~ w ~
~ R c.

~ fl ~ u c, L y y a u 8 y ' d ~

m m ~p 3 O ~ O

dr d'P A 0 3 A a p~

SUBSTITUTE SHEET (RULE 26) m m 7 b m a O A

a ao a ..a m .-i L

C !~

y ~i v v CT C p~ t a v -~ y ~ rr L

> -, y E W 1) ~ W

~ D 7 w R C 4 d O ~ 0 dr C

~ y C w v ..r ~ C m y t w ~ t1 ~

O

y m ~ C
m w ., .
r .~
E-~

v . v O
G

4 " D

QI d ~ E t C 4 4 7, y . y to pv ~ 4 U
~

v w .
C
I

s .. .. dr _ ~ .-~

.
..
C

m v dr _ . . .
~o ~ . _ b v _ . . ~ y dr o . ....
. (~
., ' E w ~ - > .. .-. G
~ ,p .

.. GI C1 ' .. .-. ~. p - p i,Ol a .a ~ ~ .r rr >
>

~; p. E i > a ~ ~ ~ t f > >

o ~ y ... w ~ ~ ~ ~ ~
= ~

ai o ~ ~. .i ~ it .
G p ~i ai G

a v . - ,, ." w ... w E ~ ~ .. > w oo ..-) ~ > a 0 a ~ 0 r . .-, x ...., ~ d .., ~' y ~ a ac o v v oc ~ ~ ~ ~ 1 ~ ~

d ~ ~ ~ y y ~ x ~

~ t v at ac ~. x . 7 v ~, y X ~ ~
~,) pe d 'v t t L ~ s _ y t opt E an y 0 a a v ~ ~- ~ ~ w G y a v a x ae ~

p a ~, ~, (~e ~e sc -~
a -. ac b v (~
a w t w c ~ y a a a a ae : V .'~ y ~ ~

~ m ~ ~ d ~ ~
d A a 7 ~ ro m x y v !C a a~ Ir Ir t U YC ?C 01 a 'O v X

a a v~ v~ a y y v v y y v v >
>

v a w w ~0 ~7 dr ~..
w SUBSTITUTE SHEET (RULE 26) -15, -m E
.O
d y m v C
E E E

y L L V

~ y y >, ro C ..

> amp ro ~

_ 6 ' O 4!
m .~
o N 41 >

.~ o ~ m 4 r~ 7 'O 'd ~

.-ro~ D fi OE .-v~ ~ . it O 8 0 .~ o e L 4 .1 U d a i ~
~ t a ~ ~
d a L dI y L .. N
m .~ N U
Lv ro y d U U i ~ P

t a m x 3 C C
p -'O
m R

. ~w C
O~ ~
~B

e w .., y - D

0 ~ & dG dP ' ~ O U
~ A

v ~ % - ' ~V
y y ~
C pp ~ ... , b t V
r a D~
i ~ y ~
a .rdP d y m ~ a C

~ p ~
.aE w .) V y m m - .. 0 O

O y ~ ro a e G~ 'O - ro D
% '0 y C1 ~ ~ ~ r~ L7 " O U

.v>. m 0, 3 8 ~
' C ~r it ~, r. !~ v y Z m 3 i i i d > u d G

orE 8 y a '~0 y Z ~ .
- 41 m ~ a .- v z U~
~

~ 0 ~r~ > ~ UvyG
~d~ ' x 1 O 41 a O y y ,ar r 0 N U a C
y ~ t, U
'~' ~

p,. . 'C w A a y o y .sr . s~ b d E
0 3 0 ~ r C

Q a o a O i m y 3 ~ o 4 at O y C a ~ m O a E O
at 01 t a ~ r E ro oG
Z b O .~ O~ O U
m a N
ro ~ . w w ~ - v Z '$ > 'g V ago o a o 3 ~ ~ ~ ~ a V
~i > m _ 8 -~ V .p OiC
3 3~YC > 01 CTm ~ ~
'eG~

C ' >m a IC 8-aC

~
a a ZZ

r.im G ~ G, Z .m ~> O 4 ZyEo ., cG
~

a Y,y ~ O, ~. ... - - Z ~.. o U C
4 >, y m ta. V r +
t ~ o ~ ~~a ~ W~
o ~ - ~ x Vr ja miro c >,. o c~ m . s .-. --.
~ ~ ~ o r ro -.c x y m o o a a ~ oc -- --~ ~p .. ...
~ > p ..
r ~.
.

, d y ~ a ~ C x x t 04 0, a1 v U O x y a '-' - a _ r w ..~--r, .,y s~~a ~ r o a r ~ o c v~

_x E. > > gx o _ $$
r r ~ > . 'a __ ~
y >

% d ',' '.' ~ " 3 G1 ~ ai a B 8 ~ 7C ~t > ~ ~
U
~

> r m r O O -~ % m m ~r .i tr v~
3 3 a ~C1 -i a a at ~

m O - - - Z 7 t C C
r~ '0 'C w V a Z y C ~
w m +
>
a ~ U7 w 3w ~ i w ~ ~~ O~' ~ C
' ' ~

~ ~ ...~
U .

w u w w r d SUBSTITUTE SHEET (RULE 26) WO 98/19253 PCT/US97/193b2 L

d . .

,..~ ..
.

,.~ ..

ro L
a a a a a a a~ : ~ ~ o y U ~ .
~

g ,, "
b , ~
U

a x x ro ~.
d .

a C ~ o ~ v V
z , m ~ a a a a .-. m -, --a x a ~ o a z ro y H- - ro 3 4 C ar o. b ~ C V

_ i0 01 a ~ U
U y - y r.i~p .. Cs. al w p, .-~
>
C
C

r d v U ~ a C y~ G
C

y a a .-. r .. .., 01 b 1a a..~ L
G I
~
E
~

a O O m 41 r~ 3 'p .-) ~
O

c a o,x ~ ~ x c ro y a E

I E E a c ro . -.
o a ~i >
o a o o a a o.
~c a z a a E V V a G . . ii a C a m --d , b ~ C ~ C y U ~ A
~
~

C .-. .-U ~ a a G
C a a E a I
- C
U
+
a O 'C7 t701 C L O L
.-. O
'C

C

a ~ ~ ~ a ~ ~ 3 ~) a nro ' E
.' G
y $

, _ C . , ( , x . a 01N ! ~ y U ...
a~ i U
C
a C
~

C > > W y V C
.r y y ...
O
G
V
~

I O 3 .a .raJ C a1 ... a a1 1 01 C x al <
a 'C7 a -~

~ C G ro ro-~ a .- ~ a ~ y > > m a y .
.~ A f C a~ C ~, ~ ~. G O ~ ~ ..
o ~ .i >
~
~ E
~
O

a . ~ .r ~ d ~ ~ c . . ~ y 3 ~
m . a ~
> a V m a E ~.

3 . v P y ~ 0G ~ ~.
C ~ .. G G ~ O ~ .r v~ a ~ ~ ., - a ro L
O a ~
a a L
v~
G
'O

~ - . . C V 'g ~ .
O O V ~ '~CI OG E~ 3 V a Z t U s D, > .m, .-a O , C -- 'C .
-~ .i " t C
O t -~
E
-, ~C
~
a ~r ow _ -. -~~ ~~~o vx ~
c L.. ~ 0. a.~ ' V G
C x ew x a ro 'G
a t7 t a -i d _:~~'%b a = ~ o x x x~ :o ~b ~vc e I
o~~o .......e~ ~~~o ~x~... o00 ~ cro,'~u oa o c oe ~
v d x a ~ o 3 $ a a x x a a x r~ ~ m ~ ..r a ~
d .r L1 y m o a d a r~
a a~
ar a a y ai . , a O ~ a.i y C ~ ~ ~ ~ a O ~ p ..a ..~ y ~7 -a ~
..r .., ~, ;
., ..a a .-1 r1y L !r L
~
CI
L

1r Ir V
a Ir lr ~E33333233 ~3~ 3 C~ ~ y ~
#3 3 a . .. 3 r i 4 4 !r lr Ir L

~

3 dr drd1 = 3 3 3 3 dr 3 dr SUBSTITUTE SHEET (RULE 26) T.
m _U
o - -C
.i m C -_ d - .i _ H

y .r L
a.
3 .~
-a x k ww ~ r m d ar d y ~
~ .r fr N

SUBSTITUTE SHEET (RULE 2fi)

Claims (19)

Claims
1. A computer method for processing medical/clinical data comprising a natural-language phrase, the method comprising parsing the natural-language phrase and regularizing the parsed phrase, wherein parsing comprises referring to a domain parameter whose value is indicative of a medical/clinical domain from which the data originated.
2. The method according to claim 1, further comprising preprocessing the data prior to parsing, with preprocessing comprising referring to the domain parameter.
3. The method according to claim 1, further comprising encoding at least one term of the regularized phrase, with encoding comprising referring to the domain parameter.
4. The method according to claim 1, further comprising filtering the regularized phrase.
5. The method according to claim 1, further comprising referring to an additional parameter which is indicative of the degree to which subphrase parsing is to be carried out.
6. The method according to claim 1, further comprising referring to an additional parameter which is indicative of desired filtering.
7. The method according to claim 1, further comprising referring to an additional parameter which is indicative of a desired type of output.
8. The method according to claim 1, further comprising referring to an additional parameter which is indicative of a desired output format.
9. A computer system for processing medical/clinical data comprising a natural-language phrase, the system comprising means for parsing the natural-language phrase and means for regularizing the parsed phrase, wherein the parsing means comprises means for referring to a domain parameter whose value is indicative of a medical/clinical domain from which the data originated.
10. The system according to claim 9, further comprising means for preprocessing the data prior to parsing, with the preprocessing means comprising means for referring to the domain parameter.
11. The system according to claim 9, further comprising means for encoding at least one term of the regularized phrase, with the encoding means comprising means for referring to the domain parameter.
12. The system according to claim 9, further comprising means for filtering the regularized phrase.
13. The system according to claim 9, further comprising means for referring to an additional parameter which is indicative of the degree to which subphrase parsing is to be carried out.
14. The system according to claim 9, further comprising means for referring to an additional parameter which is indicative of desired filtering.
15. The system according to claim 9, further comprising means for referring to an additional parameter which is indicative of a desired type of output.
16. The system according to claim 9, further comprising means for referring to an additional parameter which is indicative of a desired output format.
17. A combination of the system according to claim 9 with an interface module for enabling the system to receive input from and/or to produce standardized output for the World-Wide Web and/or a local network.
18. The combination according to claim 17, further comprising means for viewing the output using a standardized browser.
19. The combination according to claim 18, wherein the browser is a Web-browser.
CA002277123A 1996-10-28 1997-10-28 System and method for medical language extraction and encoding Abandoned CA2277123A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/738,889 1996-10-28
US08/738,889 US6055494A (en) 1996-10-28 1996-10-28 System and method for medical language extraction and encoding
PCT/US1997/019362 WO1998019253A1 (en) 1996-10-28 1997-10-28 System and method for medical language extraction and encoding

Publications (1)

Publication Number Publication Date
CA2277123A1 true CA2277123A1 (en) 1998-05-07

Family

ID=24969910

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002277123A Abandoned CA2277123A1 (en) 1996-10-28 1997-10-28 System and method for medical language extraction and encoding

Country Status (8)

Country Link
US (1) US6055494A (en)
EP (1) EP0929870B1 (en)
JP (1) JP2002515148A (en)
AT (1) ATE262703T1 (en)
CA (1) CA2277123A1 (en)
DE (1) DE69728282T2 (en)
ES (1) ES2218670T3 (en)
WO (1) WO1998019253A1 (en)

Families Citing this family (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6182029B1 (en) * 1996-10-28 2001-01-30 The Trustees Of Columbia University In The City Of New York System and method for language extraction and encoding utilizing the parsing of text data in accordance with domain parameters
US6738096B1 (en) 1998-07-10 2004-05-18 Silverbrook Research Pty Ltd Low-cost disposable camera including print media carrying indication of postage paid
AU9513198A (en) * 1997-09-30 1999-04-23 Ihc Health Services, Inc. Aprobabilistic system for natural language processing
US6915254B1 (en) 1998-07-30 2005-07-05 A-Life Medical, Inc. Automatically assigning medical codes using natural language processing
AUPP577298A0 (en) * 1998-09-09 1998-10-01 Oon, Yeong Kuang Dr Automation oriented health care delivery system based on medical scripting language
US6594634B1 (en) * 1998-09-14 2003-07-15 Medtronic Physio-Control Corp. Method and apparatus for reporting emergency incidents
US6314125B1 (en) * 1998-12-09 2001-11-06 Qualcomm Incorporated Method and apparatus for the construction and transmission of binary quasi orthogonal vectors
US20020049612A1 (en) * 2000-03-23 2002-04-25 Jaeger Scott H. Method and system for clinical knowledge management
WO2001093178A2 (en) * 2000-05-31 2001-12-06 Fasttrack Systems, Inc. Clinical trials management system and method
US7444293B1 (en) * 2000-05-31 2008-10-28 Fasttrack Systems, Inc. Protocol disambiguation using a model-based methodology
US6658377B1 (en) * 2000-06-13 2003-12-02 Perspectus, Inc. Method and system for text analysis based on the tagging, processing, and/or reformatting of the input text
US20020082868A1 (en) * 2000-12-27 2002-06-27 Pories Walter J. Systems, methods and computer program products for creating and maintaining electronic medical records
US7249018B2 (en) * 2001-01-12 2007-07-24 International Business Machines Corporation System and method for relating syntax and semantics for a conversational speech application
US7366759B2 (en) * 2001-02-22 2008-04-29 Parity Communications, Inc. Method and system for characterizing relationships in social networks
US7181017B1 (en) 2001-03-23 2007-02-20 David Felsher System and method for secure three-party communications
GB0108213D0 (en) * 2001-04-02 2001-05-23 Glaxo Group Ltd Medicament dispenser
GB0108208D0 (en) * 2001-04-02 2001-05-23 Glaxo Group Ltd Medicament dispenser
GB0108215D0 (en) * 2001-04-02 2001-05-23 Glaxo Group Ltd Medicament dispenser
GB0108228D0 (en) * 2001-04-02 2001-05-23 Glaxo Group Ltd Medicament dispenser
US7120646B2 (en) * 2001-04-09 2006-10-10 Health Language, Inc. Method and system for interfacing with a multi-level data structure
AU2002315143A1 (en) * 2001-06-13 2002-12-23 American Cardiovascular Research Institute System and method for managing data and documents
US7711581B2 (en) * 2001-08-15 2010-05-04 Andrew David Hood Customizable handheld computer data collection and report generation software
EP1288838A3 (en) * 2001-08-30 2006-06-07 Siemens Aktiengesellschaft Patient information system for annotating medical results
US7194402B2 (en) 2002-01-09 2007-03-20 International Business Machines Corporation Method and system for converting files to a specified markup language
CA2477689A1 (en) * 2002-03-05 2003-09-18 Siemens Medical Solutions Health Services Corporation A dynamic dictionary and term repository system
US7028038B1 (en) 2002-07-03 2006-04-11 Mayo Foundation For Medical Education And Research Method for generating training data for medical text abbreviation and acronym normalization
WO2004049192A2 (en) 2002-11-28 2004-06-10 Koninklijke Philips Electronics N.V. Method to assign word class information
EP1588277A4 (en) * 2002-12-06 2007-04-25 Attensity Corp Systems and methods for providing a mixed data integration service
US20040116470A1 (en) * 2002-12-16 2004-06-17 Nickel Alfred A. Novel use of ion channel active compound, meperidine, to mediate process of accelerated wound healing
US7233938B2 (en) * 2002-12-27 2007-06-19 Dictaphone Corporation Systems and methods for coding information
US9818136B1 (en) 2003-02-05 2017-11-14 Steven M. Hoffberg System and method for determining contingent relevance
US7958443B2 (en) 2003-02-28 2011-06-07 Dictaphone Corporation System and method for structuring speech recognized text into a pre-selected document format
US8095544B2 (en) * 2003-05-30 2012-01-10 Dictaphone Corporation Method, system, and apparatus for validation
US20040243545A1 (en) * 2003-05-29 2004-12-02 Dictaphone Corporation Systems and methods utilizing natural language medical records
US20040243552A1 (en) * 2003-05-30 2004-12-02 Dictaphone Corporation Method, system, and apparatus for viewing data
US8290958B2 (en) * 2003-05-30 2012-10-16 Dictaphone Corporation Method, system, and apparatus for data reuse
US8504380B2 (en) * 2003-06-05 2013-08-06 Medidata Solutions, Inc. Assistance for clinical trial protocols
US20050027564A1 (en) * 2003-06-18 2005-02-03 Yantis David Brook Term management system suitable for healthcare and other use
US20050120300A1 (en) * 2003-09-25 2005-06-02 Dictaphone Corporation Method, system, and apparatus for assembly, transport and display of clinical data
US7860717B2 (en) * 2003-09-25 2010-12-28 Dictaphone Corporation System and method for customizing speech recognition input and output
US8024176B2 (en) * 2003-09-30 2011-09-20 Dictaphone Corporation System, method and apparatus for prediction using minimal affix patterns
US7542909B2 (en) * 2003-09-30 2009-06-02 Dictaphone Corporation Method, system, and apparatus for repairing audio recordings
US7818308B2 (en) * 2003-10-01 2010-10-19 Nuance Communications, Inc. System and method for document section segmentation
US7996223B2 (en) * 2003-10-01 2011-08-09 Dictaphone Corporation System and method for post processing speech recognition output
US20050144184A1 (en) * 2003-10-01 2005-06-30 Dictaphone Corporation System and method for document section segmentation
US7774196B2 (en) * 2003-10-01 2010-08-10 Dictaphone Corporation System and method for modifying a language model and post-processor information
US8200487B2 (en) 2003-11-21 2012-06-12 Nuance Communications Austria Gmbh Text segmentation and label assignment with user interaction by means of topic specific language models and topic-specific label statistics
US7315811B2 (en) * 2003-12-31 2008-01-01 Dictaphone Corporation System and method for accented modification of a language model
US7783474B2 (en) * 2004-02-27 2010-08-24 Nuance Communications, Inc. System and method for generating a phrase pronunciation
US7822598B2 (en) * 2004-02-27 2010-10-26 Dictaphone Corporation System and method for normalization of a string of words
US20050203776A1 (en) * 2004-03-15 2005-09-15 Godwin Sharen A. Method of identifying clinical trial participants
US7379946B2 (en) * 2004-03-31 2008-05-27 Dictaphone Corporation Categorization of information using natural language processing and predefined templates
US7730485B2 (en) * 2004-08-10 2010-06-01 At&T Intellectual Property I, L.P. System and method for advertising to a Wi-Fi device
US8547401B2 (en) * 2004-08-19 2013-10-01 Sony Computer Entertainment Inc. Portable augmented reality device and method
US7584103B2 (en) * 2004-08-20 2009-09-01 Multimodal Technologies, Inc. Automated extraction of semantic content and generation of a structured document from speech
US8412521B2 (en) * 2004-08-20 2013-04-02 Multimodal Technologies, Llc Discriminative training of document transcription system
US8335688B2 (en) 2004-08-20 2012-12-18 Multimodal Technologies, Llc Document transcription system training
WO2006034152A2 (en) * 2004-09-17 2006-03-30 Multimodal Technologies, Inc. Discriminative training of document transcription system
US8756234B1 (en) * 2004-11-16 2014-06-17 The General Hospital Corporation Information theory entropy reduction program
WO2007005682A2 (en) * 2005-07-05 2007-01-11 Dictaphone Corporation System and method for auto-reuse of document text
US8874477B2 (en) 2005-10-04 2014-10-28 Steven Mark Hoffberg Multifactorial optimization system and method
JPWO2007102320A1 (en) * 2006-03-07 2009-07-23 日本電気株式会社 Language processing system
US7949538B2 (en) * 2006-03-14 2011-05-24 A-Life Medical, Inc. Automated interpretation of clinical encounters with cultural cues
US8731954B2 (en) * 2006-03-27 2014-05-20 A-Life Medical, Llc Auditing the coding and abstracting of documents
US10360996B2 (en) * 2006-03-31 2019-07-23 Cerner Innovation, Inc. Method for selectively associating content items with pre-configured alternatives based upon directed user input
US20070265879A1 (en) * 2006-03-31 2007-11-15 Cerner Innovation, Inc. Method for automated configuration, implementation and/or maintenance of a healthcare information system
US20080015895A1 (en) * 2006-03-31 2008-01-17 Cerner Innovation, Inc. Automated configuration, implementation and/or maintenance of a healthcare information system
US7831423B2 (en) * 2006-05-25 2010-11-09 Multimodal Technologies, Inc. Replacing text representing a concept with an alternate written form of the concept
WO2007150005A2 (en) 2006-06-22 2007-12-27 Multimodal Technologies, Inc. Automatic decision support
US10796390B2 (en) * 2006-07-03 2020-10-06 3M Innovative Properties Company System and method for medical coding of vascular interventional radiology procedures
US8346555B2 (en) * 2006-08-22 2013-01-01 Nuance Communications, Inc. Automatic grammar tuning using statistical language model generation
WO2008112548A1 (en) * 2007-03-09 2008-09-18 The Trustees Of Columbia University In The City Of New York Methods and system for extracting phenotypic information from the literature via natural language processing
US7908552B2 (en) 2007-04-13 2011-03-15 A-Life Medical Inc. Mere-parsing with boundary and semantic driven scoping
US8682823B2 (en) 2007-04-13 2014-03-25 A-Life Medical, Llc Multi-magnitudinal vectors with resolution based on source vector features
US20080300922A1 (en) * 2007-06-01 2008-12-04 The Children's Mercy Hospital Electronic medical documentation
US9946846B2 (en) * 2007-08-03 2018-04-17 A-Life Medical, Llc Visualizing the documentation and coding of surgical procedures
US9864838B2 (en) * 2008-02-20 2018-01-09 Medicomp Systems, Inc. Clinically intelligent parsing
US8600772B2 (en) * 2009-05-28 2013-12-03 3M Innovative Properties Company Systems and methods for interfacing with healthcare organization coding system
US20100305969A1 (en) * 2009-05-28 2010-12-02 3M Innovative Properties Company Systems and methods for generating subsets of electronic healthcare-related documents
US10586616B2 (en) 2009-05-28 2020-03-10 3M Innovative Properties Company Systems and methods for generating subsets of electronic healthcare-related documents
US8219519B2 (en) * 2010-02-23 2012-07-10 GM Global Technology Operations LLC Text extraction for determining emerging issues in vehicle warranty reporting
US8959102B2 (en) 2010-10-08 2015-02-17 Mmodal Ip Llc Structured searching of dynamic structured document corpuses
CN103262070B (en) * 2010-12-23 2018-12-04 皇家飞利浦电子股份有限公司 The picture report signal map generalization of lesion in anatomical structure
US10032127B2 (en) 2011-02-18 2018-07-24 Nuance Communications, Inc. Methods and apparatus for determining a clinician's intent to order an item
US9679107B2 (en) 2011-02-18 2017-06-13 Nuance Communications, Inc. Physician and clinical documentation specialist workflow integration
US8738403B2 (en) 2011-02-18 2014-05-27 Nuance Communications, Inc. Methods and apparatus for updating text in clinical documentation
US9916420B2 (en) 2011-02-18 2018-03-13 Nuance Communications, Inc. Physician and clinical documentation specialist workflow integration
US8694335B2 (en) 2011-02-18 2014-04-08 Nuance Communications, Inc. Methods and apparatus for applying user corrections to medical fact extraction
US8768723B2 (en) 2011-02-18 2014-07-01 Nuance Communications, Inc. Methods and apparatus for formatting text for clinical fact extraction
US8799021B2 (en) 2011-02-18 2014-08-05 Nuance Communications, Inc. Methods and apparatus for analyzing specificity in clinical documentation
US8788289B2 (en) 2011-02-18 2014-07-22 Nuance Communications, Inc. Methods and apparatus for linking extracted clinical facts to text
US10460288B2 (en) 2011-02-18 2019-10-29 Nuance Communications, Inc. Methods and apparatus for identifying unspecified diagnoses in clinical documentation
US9904768B2 (en) 2011-02-18 2018-02-27 Nuance Communications, Inc. Methods and apparatus for presenting alternative hypotheses for medical facts
CN102194059A (en) * 2011-05-24 2011-09-21 中国科学院上海技术物理研究所 Visual indexing system for medical information system
GB2506807A (en) 2011-07-29 2014-04-09 Trustees Of Columbia In The City Of New York System and method for language extraction and encoding
WO2013082087A1 (en) 2011-11-28 2013-06-06 Voicehit Electronic health record system and method for patient encounter transcription and documentation
US8793199B2 (en) 2012-02-29 2014-07-29 International Business Machines Corporation Extraction of information from clinical reports
US9569594B2 (en) 2012-03-08 2017-02-14 Nuance Communications, Inc. Methods and apparatus for generating clinical reports
US9710431B2 (en) 2012-08-18 2017-07-18 Health Fidelity, Inc. Systems and methods for processing patient information
US8935155B2 (en) * 2012-09-14 2015-01-13 Siemens Aktiengesellschaft Method for processing medical reports
US11024406B2 (en) 2013-03-12 2021-06-01 Nuance Communications, Inc. Systems and methods for identifying errors and/or critical results in medical reports
US11183300B2 (en) 2013-06-05 2021-11-23 Nuance Communications, Inc. Methods and apparatus for providing guidance to medical professionals
US10541053B2 (en) 2013-09-05 2020-01-21 Optum360, LLCq Automated clinical indicator recognition with natural language processing
US10133727B2 (en) 2013-10-01 2018-11-20 A-Life Medical, Llc Ontologically driven procedure coding
US10373711B2 (en) 2014-06-04 2019-08-06 Nuance Communications, Inc. Medical coding system with CDI clarification request notification
US10490306B2 (en) 2015-02-20 2019-11-26 Cerner Innovation, Inc. Medical information translation system
US11152084B2 (en) 2016-01-13 2021-10-19 Nuance Communications, Inc. Medical report coding with acronym/abbreviation disambiguation
EP3516560A1 (en) 2016-09-20 2019-07-31 Nuance Communications, Inc. Method and system for sequencing medical billing codes
US11355221B2 (en) * 2017-01-09 2022-06-07 Mahdis MANSOURI Classification systems, and methods of collecting, associating, storing, searching, and providing healthcare information, and connecting healthcare participants globally
US11133091B2 (en) 2017-07-21 2021-09-28 Nuance Communications, Inc. Automated analysis system and method
US11024424B2 (en) 2017-10-27 2021-06-01 Nuance Communications, Inc. Computer assisted coding systems and methods
US20220261538A1 (en) * 2021-02-17 2022-08-18 Inteliquet, Inc. Skipping natural language processor

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4965763A (en) * 1987-03-03 1990-10-23 International Business Machines Corporation Computer method for automatic extraction of commonly specified information from business correspondence
US5251131A (en) * 1991-07-31 1993-10-05 Thinking Machines Corporation Classification of data records by comparison of records to a training database using probability weights
US5265065A (en) * 1991-10-08 1993-11-23 West Publishing Company Method and apparatus for information retrieval from a database by replacing domain specific stemmed phases in a natural language to create a search query
US5327341A (en) * 1991-10-28 1994-07-05 Whalen Edward J Computerized file maintenance system for managing medical records including narrative reports
US5377103A (en) * 1992-05-15 1994-12-27 International Business Machines Corporation Constrained natural language interface for a computer that employs a browse function
EP0599022A3 (en) * 1992-11-23 1995-02-22 Emtek Health Care Inc A method for displaying microbiological laboratory results.
NZ248751A (en) * 1994-03-23 1997-11-24 Ryan John Kevin Text analysis and coding

Also Published As

Publication number Publication date
WO1998019253A1 (en) 1998-05-07
JP2002515148A (en) 2002-05-21
EP0929870A4 (en) 2002-08-28
EP0929870B1 (en) 2004-03-24
DE69728282D1 (en) 2004-04-29
US6055494A (en) 2000-04-25
EP0929870A1 (en) 1999-07-21
ES2218670T3 (en) 2004-11-16
ATE262703T1 (en) 2004-04-15
DE69728282T2 (en) 2005-07-21

Similar Documents

Publication Publication Date Title
CA2277123A1 (en) System and method for medical language extraction and encoding
Gupta et al. Sentiment analysis of lockdown in india during covid-19: A case study on twitter
Khan et al. CoroNet: A deep neural network for detection and diagnosis of COVID-19 from chest x-ray images
Garcia et al. Topic detection and sentiment analysis in Twitter content related to COVID-19 from Brazil and the USA
Nawar et al. National hospital ambulatory medical care survey: 2005 emergency department summary
Blumenthal et al. Violence and mental disorder: A critical aid to the assessment and management of risk
Xie et al. Exploring public response to COVID-19 on Weibo with LDA topic modeling and sentiment analysis
CN109102886A (en) The disease of old people reasoning diagnostic system of more reasoning pattern fusions
CN113192624B (en) Emergency treatment system, emergency treatment method and electronic device
JP2011221683A (en) Customer service support device, customer service support method, and program
Ariza Keeping up appearances in the Argentine fertility clinic. Making kinship visible through race in donor conception
Spachos et al. Voice activated IoT devices for healthcare: Design challenges and emerging applications
CN107644023A (en) A kind of document treatment method and apparatus
CN114078592A (en) Emergency triage wisdom medical system
CN116453674A (en) Intelligent medical system
Lavender et al. Community Care in Practice: services for the continuing care client
Lavender et al. New ways of working for applied psychologists in health and social care: the end of the beginning: summary report
Leung et al. A Novel Interpretable Deep-Learning-Based System for Triage Prediction in the Emergency Department: A Prospective Study
JP2020144676A (en) Information linking system, information linking server, voice i/o device, information linking method, and program
Pedersen et al. MeDa-BERT: A medical Danish pretrained transformer model
US20230315989A1 (en) Readmission model based on social determinants of health
Hall et al. A history of clinical psychology in Britain: Some impressions and reflections
Asha et al. Sentimental analysis of lockdown in india during covid-19
US20240086771A1 (en) Machine learning to generate service recommendations
Yu The design of electronic medical records system using Skip-gram algorithm

Legal Events

Date Code Title Description
EEER Examination request
FZDE Discontinued