~-J

ì'_../

Monocenter Post Marketing Observation Study

Alphaglobin@ ATG 9410

Final Report

27.10.1995

Author:Dr. Doris WeberDrug & Regulatory Affairs Departmentalpha. Therapeutic GmbH63225 LangenFRG

alphGo_DRA_DW_DOCJlmadlpraelagllawblawb941 0\11 rpt\d951 027d.doc _ Selte 1

SECTION 9 5770

(-)

C)

1. ABSTRACT:

Data on c1inical use of Alphaglobin@ under routine conditions were documented forsix patients. AII patients were treated at the hospital of dermatology in Jena, FRG.The indications differed for every patient and were as follows: immunocytoma withherpes zoster, hypogammaglobulinemia and erythema exsudativum multiformemajus, primary immunodeficiency, panarteritis nodosa, risk of infection, andHutchinson-Gilford-syndrome with secondary immundeficiency. ".With every patient c1inical condition was assessed to be better at the end of therapycompared to the beginning of therapy.Two adverse events were observed with 34 infusions given. None of them is to bejudged as serious.

2.INTRODUCTION:

The efficacy of intravenous immunoglobulins (IVIG) in patients with primary andsecondary immunodeficiency is well established and can be explained by thepassive transfer of antibodies to provide humoral immunity.Besides, IVIG treatment has also been established in several immune-mediateddisorders, like autoimmune diseases. IVIG has shown to result in c1inicalimprovement in a number of distinct autoimmune di seas es like idiopathicthrombocytopenic purpura (ITP) and Kawasaki disease. For others c1ínicalimprovement has been suggested but needs further confirmation by controlled trials.Such indications are e.g. chronic inflammatory demyelinating polyneuropathy (CIDP)as well as its acute form the Guillain-Barre syndrome, myastenia gravis, systemiclupus erythematosus, rheumatoid arthritis, and habitual abortions.The mechanisms of IVIG action in autoimmune disorders still aren't elucidated indetail. Among others anti-idiotypic antibodies in the IVIG preparations neutralizingautoaggressive antibodies in the patient, inhibtion of antibody producing B-Iymphocytes and block of Fc-receptors are discussed as possible mechanisms ofaction of IVIG.

Ongoing and further investigations surely will develop several other areas ofapplication for intravenous immunoglobulins.Intravenous immunoglobulins were for a long period regarded as safe concerning thetransmission of viruses.The broad use of IVIG has shown however, that transmissionof hepatitis B as well as hepatitis C could not be excluded.To assure safety, the introduction of specific virus inactivation/elimination stepsduring the manufacturing process is needed.Alphaglobin@ is a liquid pasteurized intravenous 7S-immunoglobulin. The liquid-heattreatment (60°C for 10h) is included into the production process of Alphaglobin@

because of its efficacy in inactivating Iipid coated as well as non-lipid coated virusesThis method guarantees virus safety without modifying the IgG molecule.

alphGo_DRA_DW_DOCJlmadlpraelagllawblawb941 0\11 rpt\d951 027d.doc _ Seite 2

SECTION 9 5771

, -)

, ). /

3. OBJECTIVE:

This post marketing observation study (PMOS) was performed to get informationabout application of Alphaglobin@ under routine conditions. The main question washow Alphaglobin@ is tolerated. In addition, clinical efficacy could be judged by thedoctor.

4.PATIENTS, EXAMINATIONS, AND METHODS:

This report deals with data ascertained in the department ofPrivo Ooz. Dr. medo habil. U.WollinaKlinik für OermatologieErfurter Str. 3507740 Jena6 patients were included and treated between September 1994 and March 1995.For every patient demographic and anamnestic data (indication, concomitantdiseases, concomitant medication) were ascertained.With every infusion the doctor was asked to document date, lot and dosage ofAlphaglobin@, length of infusion, blood count (if ascertained), changes in c1inicalcondition and in concomitant medication and adverse events.Ouring the first infusion, body temperature, respiratory rate, heart rate and bloodpressure could be documented.In addition, the investigator had the possibility to describe any further observationsbefare, during and after the treatment cycle.After treatment was finished the doctor had the possibility to judge efficacy,tolerability and virus safety of Alphaglobin@ by a score (good, moderate, bad) and togive information whether the condition of the patient has improved, is unchanged,deteriorated or whether it is not judgeable.In case of adverse events occurring a description and evaluation was asked foro

5. RESULTS:

Patients, Indications, and Concomitant Drugs:6 patients (3 female, 3 male) ranging in age from 11 to 65 years (mean 46.8 years)were included. Indications were different with all patients. They are listed togetherwith concomitant diseases of the patients in table 1.Concomitant drugs the patients received are Iisted in table 2.

Infusions, Dose:For four patients 6 infusions were documented, the remaining two patients receivedonly 5 infusions. AII patients were treated as in-patients.They received 47 to 240 mg Alphaglobin@ per kg body weight (table 3). Each patientreceived the same dose for every of his five or six infusions.

alphGo_DRA_DW_DOCJlmadlpraelagllawblawb941 0\11 rpt\d951 027d.doc _ Seite 3

SECTION 9 5772

The infusions were given one after the other day except for patient no. 6, whoreceived the last infusion one month after his fifth infusion.

Vital signs:Vital signs were documented befare and at 10,30,60, 120, and 240 minutes afterthe beginning of the first infusion. For patient no. 3 sorne data on temperature andrespiratory rate are missing, for patient no. 4 all data at 240 mino are missing.Changes in vital signs didn't exceed 8 inspirations in respiratory rate, 30 mmHg insystolic blood pressure and 20 mmHg in diastolic blood pressure. Oifferences inbody temperature were maximum 1,6 oC, a difference seen with patient no. 5. Hisbody temperature was 39°C befare the infusion was started and 37,4°C 240 minafter the beginning of infusion (which was about 3 hours after the end of infusion).Heart rate showed differences of up to 32 beats. This was documented with patientno. 4. His heart rate was 116 beats/min. befare the infusion started and decreased to84 beats/min. during infusion. At the end of infusion his heart rate had increasedagain to 108 beats/min..

( )

Conspicuous clínical findings before the beginning of therapy:Information on conspicuous clinical findings documented by the doctor beforetherapy was started is summarized in table 3.

Laboratory Findings:The judgement of the blood count, which could be documented befare the initiationof treatment and after each infusion, was based on limits of normal given in theliterature (see appendix).Results of the blood count are summarized in table 4. Since all patients receivedtheir infusions one day after the other blood count wasn 't documented with everyinfusion, except for patient no. 2. Therefore an analysis of these data is difficult toperform.Changes in the leukocyte count could be detected with sorne patients duringtreatment although there was no unique trend (decrease or increase) to be seen.With patient no. 1 the leukocyte count was slightly above the normal range after the5th infusion. This is perhaps due to his underlying disease (immuncytoma).

Safety (Tolerability):Two adverse events (AEs) were documented with 34 infusions.Patient nO.1 showed a hypertone reaction up to 230/100 mmHg after the fifthinfusion, which was known from anamnesis and occured about 12 hours afterinfusion. The event lasted for two hours and was c1assified as moderate by thedoctor. The patient received a antihypertensive drug. A correlation between the AEand Alphaglobin@ was judged to be unlikely by the doctor .Patient no. 2 showed fever after the sixth infusion and a massive tarry stool. Thedoctor described an increasing catabolism under therapy, which in his opinion wasn'tcorrelated to medication.

alphGo_DRA_DW_DOCJlmadlpraelagllawblawb9410\11 rpt\d951027d.doc _ Selte 4

SECTION 9 5773

Effcacy: .At the end of treatment the c1inical condition of the patient was judged as "better"with all patients. Efficacy, tolerability and virus safety were considered to be "good"with every patient.Further information given by the doctor concerning efficacy is summarized in table 3.Unfortunately the comments given by the doctor are rare with most patients. Patientno. 1, who suffered from an immunocytoma and a generalized herpes zosterinfection was free of pain at the end of treatment. Patient no. 5, who received fiveinfusions of Alphaglobin@ because of generalized psoriasis postulosa and the .therefore high risk of infection showed decrease of fever after the 1 st infusion and animprovement of skin and general c1inical condition after he received the 4th and 5th \infusion.With patient no. 6, an 11 year old boy with Hutchinson-Gilford-syndrome andsecondary immundeficiency, who suffered from extensive ulcerations, theinvestigator documented, that the aim of avoiding infections was reached by theIVIG-therapy. Ulcerations remitted and the general condition of the boy wasstabilzed., -)

6. DISCUSSION:

\

Six patients received a total of 34 infusions of Alphaglobin@ during this drugmonitoring.As far as evaluaLion of efficacy is concerned this PMOS does not result in majar newfindings. The investigator gave only few comments concerning effieacy aside fromhis assessment given in the prepared graded sheet. Therein he judged the c1inicalcondition to be better at the end of therapy compared to the beginning of therapywith every patient. Nevertheless for three patients further positive statementsregarding efficacy of therapy are given. For the other three patients no commentsare available.Two adverse events were observed with 34 infusions given. One of them, ahypertone reaction which occured 12 hours after the 5th infusion, was documentedas AE by the doctor. He judged a correlation between the AE and Alphaglobin@ to

be unlikely. The other AE, a massive tarry stool and a rise in temperature could notbe attributed to Alphaglobin@. it occured after the 6th infusion with another patient.

None of the AEs is to be judged as serious.The changes in vital signs during the first infusion documented in this PMOS were .greater than those observed during other drug monitorings with Alphaglobin@. This isperhaps due to the serious underlying diseases most of the six patients suffer from.as well as the extensive concomitant medication.Taken together the results obtained from this PMOS show, that Alphaglobin@ was .well tolerated and as far a assessable by these data met the requirementsconcerning efficacy.

alphGo_DRA_DW _DOC Jlmadlpraelagllawblawb941 0\11 rpt\d951 027d.doc _ Seite 5

SECTION 9 5774

APPENDIX:

E ryh rocy tes milI. 1 ~I

Leukocytes 1 ~I

Thrombocytes x 1,000 1 ~I

Hemoglobin mmol/l

Hematocrit %)

Range of Normal

male female

3.9 - 5.34.3 - 5.7

3,800 - 10,500

140 - 345

8.37 -10.54

40-52

7.44 - 9.92

37 -48

from: Herold, G (ed.): Innere Medizin (1989), Köln

alphGo_DRA_DW_DOCJ\madlpraelagllawblawb9410\11 rpt\d951 027d.doc _ Seite 6

SECTION 9 5775

rn m o -4 I- O Z U)

U' .. .. al

AWB9410\T950728E.xLS -

Tab

le 1

: Dem

ogra

phic

dat

a, I

ndic

atio

ns, a

nd C

onco

mita

nt D

isea

ses

of P

atie

nts

Dem

ogra

phic

Dat

a, In

dica

tions

, and

Con

com

itant

Dis

ease

s of

Pat

ient

sPa

tlen-

Nr.

Inltl

als

Age

(ye

arsJ

Sex

Dia

gnos

isIn

dlca

tlon

Con

com

o D

lsea

se

1H

A65

fG

ener

aliz

ed h

erpe

s zo

ster

,Im

mun

ocyt

oma

with

zos

ter

Diabetes melltus, Chron. ischemic heart

imm

unoc

ytom

adi

seas

e, s

trum

a

Hyp

oam

mag

lobu

linem

ia a

ndH

ypog

amm

aglo

bulin

emia

and

Rhe

umat

oid

arth

ritis

, hyp

erto

nia

and

hear

t2

LH

63f

eryh

ema

exsu

dativ

umer

yhem

a ex

suda

tivum

mul

tifor

me

dise

ase,

nep

hrot

ic a

myl

oido

sis

mul

tifor

me

maj

us

3R

S27

fS

uspe

cted

X-I

inke

dP

nm. i

mm

unod

efic

ienc

y sy

ndro

me

Perl

èche

agam

mag

lobu

linem

ia

Chr

on. i

sche

mic

hea

rt d

isea

se (

CIH

D),

Con

d.

4K

U51

Pana

rten

tis n

odos

a an

dPa

nart

entis

nod

osa

afie

r re

sect

ion

of 2

13 o

f sto

mac

h, c

atar

act

mhy

poam

mag

lobu

linem

iabi

late

ral,

cond

. afi

er r

esec

tion

of s

trum

ana

dosa

, acu

te r

espi

rato

l) in

fect

ion

5E

G64

mGeneralized psonasis postulosa

Ris

k of

infe

ctio

nC

ond.

afie

r su

rger

y of

bas

ilom

a (r

ight

med

ian

com

er o

f th

e ey

e)

Hut

chi n

son-

Gi I

ford

-syn

drom

eH

utch

inso

n-G

ilfor

d-sy

ndro

me

with

6E

M11

mw

ih s

econ

dal)

secondal) immunodeficiency

Exe

nsiv

e ul

cera

tions

due

to b

asic

dis

ease

imm

unod

efic

ienc

y...

Seite 1

AVVB941 0\T950731 D.XLS

Table 2: Concomitant drugs

Concomitant Drugs

Group Preparation Patient-No.Antihypertensives Physiotens 0,4 1

ACE-Inihibitors Dynacil 1

Cor tensobon 2Calcium antagonists Corinfar 1 (since 5th inf.)Beta blockers Obsidan 25 2Cardiacs Digitoxin 1

Diuretics Lasix 2Drugs stimulating the blood f10w Trental 4,6Coronary stimulant Pentalong 4Thvroid hormones L-Thvroxin 100, 175 1,4Antidiabetics Maninit 1 1

Glucobav 1

Muscle relaxant Musanl 1

Antianemic drugs Recormon 2Analgetics / Antirheumatics Rewodina 2

Paracetamol 5 (until 4th inf.)Lantarel 5 (since 5th inf.)

Corticoids Prednisolon 2Decortin 10 mg 4Prednisolut 5 (since 1 st inf.)

Infusions and standardinjections Sodium-bicarbonate 2(since 1 st infusion until

2nd infusion)Human albumin 2 (since 4th inf.), 5

Antibiotics / chemotherapeutics Fortum 2 (since 6th inf.)Doxyeyelin 5Zovirax 1

Antimyeotics Diflucan 50 2Moronal Dm. 3

Mouth and throat therapeutics Moronal suspension 3Hvonotics / tranauilzers Planum 3Gastro-intestinal drugs Salofalk 3

Cerueal 3 (only after 2nd inf.)Ulcogant 4

Gynecological drugs Gynoflor 3 (since 3rd inf.)Jenamazol 3 (since 3rd inf.)

Spasmolvics Buseopan 4Urologicals Harzol 4Ophthalmics Gentamvcin Augentropf. 5 (since 1st inf.)Dennatics Neobonsen 6Minerals Zinkorotat 6Others E 153-lnfusionslösung 5 (until 2nd inf.)

Proten plus 3 (since 5th inf.)Soasman Iiauidum 3

Seite 1

SECTJ:ON 9 5777

~xciro~oLO(lt:O..-aoi

~

-k~!EQ)

-galenc:O.ui.a.5c:o~Q)

EE8'Cc:alal-aloC'Q):õall-

£oS

al1i

~ë!

~ gÆ!

.!! l'112: "" E- . _ 2: .l L;

16 10 g ~-r "O~ 2-

'õË 5- ~ !!1: 5 :! ;¡ ~

'8 '8 '8oi.8 .Q

2l~ N E J1 ~ 110 al ci oi oi

O R .. I. ~ Eca -

~i ~ giO lO .l~lE

w '".2!g¡

o.~

W 10 j;~"C

E'":5

c: gica 'C::oøc: ,.O 10 ~

"E.-L

'Jen

L

,ñ:s Gl 2!.. o E

c:C 10

'õ ,ñ e10- tIe e E

c:o ëii

H~

'"

O ~2: ~ ~

8,J!ë6 e", a.'t"O Cl L;

2i,. -

Ioi o "O W e

c: oi lO "O ~~ .2e "t ,. ~1 1 8.- II 10

CI.a ~.§ e

1î~ m:i lO.. e oi

fi o 8~E l' .. '" 'ii.. ti rJ ti

ai- ~z :: oE 8 O j z

U) Š =O

o lO.a .~ - L;

O £ 11g-~e

E 1i o

"C E!o

1tflL ::

c: ë~ca

:s§rJ

ca l 1.. Cl :iOcae Gloi

£§ :So ~ 'õ- .2 ~ -g~ Æ; w

~ CP CP ~11 11

'"

git=.2 ~ ~ ~ ~ ~ ~ :5 ~

Ji.a .8 5 it = =

1ä .§= et

h.E - 'õ lO ~ lO .§ lO e lO .§ lO e il i~ i~å

~ ~~ gi l1.2 ~ .2z l1- i !l l1 l1 ø i øCl ø Cl~ Cl !l ., øi: JI E .a ~ .2 E -E

§~1- - 1- .a

~ IE.. E_ E 'E~ ~i .. ~JI E- E .E 6.E ~~

E- S ~ ~~1i :: 51 o l¡ O~ 8~ ~~ ~5el zn: om O.. O~ O~ 01- o: O o: W

SECTION 9

..~'IDen

5778

o m O -l 1- O Z 10 en ~ ~ 10

AW

B94

10\T

9507

28D

.XL

S

--!

Dat

aand

Com

men

ts o

n In

fusi

ons

and

Effi

cacy

(2)

Patle

nt-N

o.3

4N

umbe

r of

Infu

sion

s I D

osge

6 I 113.7 mgJg daily

6I 47.6 mglkg daily

Reg

lmen

Skin

: Mac

ulae

, hyp

erpi

gm.,

vari

cois

low

r le

g; E

yes:

Bila

t. ca

tara

ct, r

.C

linlc

al F

lndl

ngs

Bef

ore

the

slde after surgery; Nosroa: Cond. after surg. or struma, chron.

Beg

lnnl

ng o

f The

rapy

rhln

itis;

Res

p. S

yst.:

Chr

on. b

ronc

hits

; Hea

rtC

írc.

: CIH

D; G

a51r

oint

.:Cond. after 21 reset. or 510mach

Com

men

t beo

re1s

t Inf

usío

n

Com

men

ts a

rter

1.ln

fusl

oComments affr

2.ln

fusl

onC

omm

ent a

fter

3.ln

fusl

onC

omm

enta

rter

4.ln

fusl

onC

omm

ent a

fter

5. lnruslon

Com

men

t afte

r6.

lnru

slon

Comments at th End of th

Treatmet Cycle

Afte

r T

rent

:be

erbe

tter

Clin

lc S

tatu

Aft

Tre

nt:

goo

goo

Efr

caA

fter

Tre

ant:

,

Tol

erab

llit

goO

goo

Afte

r T

reat

men

t:go

Ogo

oV

irus

sfet

y

.;

Sei

te 2

rn m o -l 1- o Z U)

U1 .. (X o

AW

8941

0\T

9507

28D

.XL

S

Dat

a an

d C

omm

ents

on

Infu

sion

s an

d E

ffica

cy (

3)Pa

tnt-

Na.

56

Num

be o

f In

fusl

o I

Dos

ge5 I 80 rng dally

6I

240

mgl

kg, 5

infu

slon

s da

lly, 6

th in

fusi

an 1

mon

th la

ter

Reg

lme

Skl

n: P

re e

ryro

derm

la a

nd p

us1u

lois

;S

kin:

Exe

nsiv

e ul

cera

; Eye

sars

: Beg

lnnl

ng e

cpio

n; N

oseI

hroa

:C

línlc

al F

lndl

ng B

efor

e th

eA

nkyl

osls

of c

ervc

al s

plne

; Che

s: F

lat t

hora

; Abd

omen

: Pat

ch Ii

keB

ennl

n of

Thp

yEyears: Perslsent defec afler hellng and surgery of basa

lom

a plaques; Exmitles: Formon of ankyoses

Com

men

t beo

reL

arge

chr

onic

wou

nds

wih

fur

1 st

Inf

uslo

n

Com

men

t afte

rD

ere

of fe

ver,

no

effe

c on

psr

iasi

s1.

lnfu

slo

Com

men

t afte

rN

o fe

ver

any

long

er2.

lnfu

slon

Com

men

t afte

rIm

proe

men

t of c

linic

al c

onltn

3.ln

fusl

onC

omm

ent a

fter

Con

tinul

ng im

prov

emen

t of c

linlc

al c

ondi

tion,

no

ne g

ener

aion

of

4.ln

fusl

onpu

s1ul

eC

omm

ents

afte

rC

onnu

lng

Impr

ovm

ent o

f clin

ical

con

ditio

n an

d sk

ln, r

eres

sion

of

5.ln

fusl

onsw

llen

Iyph

node

sComments al'

Ulc

era

less

fure

d, s

hrin

klng

of t

he w

ound

are

a ob

jecv

ely

mea

urab

le,

6.ln

fusl

oncl

inlc

al c

ondl

tn s

1abl

e

Short term dramac improvemen of th dlsee wa no expted wih

Com

men

t at t

h E

nd o

f the

thls

indi

caon

. The

mos

Im

pont

alm

was

to a

void

an

Infe

con.

Thi

sT

rem

ent C

ycle

was

rea

hed

and

the

gene

ral c

oito

n w

as s

tblll

zed.

Afte

r T

reat

m:

beer

beer

Clln

lcal

Sta

Afle

r T

rean

t:go

ogo

oE

ffca

Afte

r T

re:

goo

9000

T olerblllt

Afle

r T

rent

:go

ogo

oV

irue

t

.)

Seite 3

~u.IXNr-O1.en!:O.."'enm

~

)

-c:::oo'8oãi

.i:o . . I . . I I . I I I I I I I I I I I'f i : 1

. 1 NN..NN : . i . I1

1 : : i I i . . 1 I : 1 i .:i i , , I . , . . I . . , , , . . . ,

~i: 0000r- . . . . . . . . . . i: i: i: i: cio .

1 I 1 i..r-OI.N 't't't't't 't't't't't i . i 1 I ¿ ¿ ¿ ¿¿

rB ~i MMIÒIÒO e: e: e: e: e: e: e: e: e: e: i I. I I I I

Ol. . I I I

E. ..'5 i i . . I .

~ ii ,

Ii

Ii

Ii

i, . ,

I..N...... NN..NN iI

. i . I i 1 I I I. . .

I I . . I I . I . . . .

~i: i-0001X NOOOIX . . . . . . . . . . . . . . . . . . . .o NC"OC"C" N.qOC"N 't't't't't 't't't't't 't't't't't 't't't'ta

.. ëñ ......còo MMolCÒO e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e:iñ -2 ..N o

E. N N,e.2 . i

II

i I. i

1i

Ii 1

ii

Ii

I I I1

.I I Iia .

1 NN..NN i i I:i . . I . . I I I I I . I

~

5 -q-q-q-q-q t:~g~~ -q-q-q-q-q -q-q-q-q-q -q-q-q-q-q -q-q-q-qa~~ e: e: e: e: e: NM"-IÒO e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e: e:

NE. N

,i:o i I . I I I I I . I I I I I ,,.al ~T'T'T'C' NN..NN I

1. I I ,. C\ '" T' T' I I I . I I I I , I

:i I I I . I I I . I I . I I .

.. ~s: i: OOOOCO 000000 . . . . . NOOOIO . . . . . . . . . .o vOlONC" ..OO..N 't't't't't Ioi-OOlv -a't't't't 't-a't'ta:: "E ëi ..i-còcòo MMIÒCÒOe: e: e: e: e: iò"-MCÒO e: e: e: e: e: e: e: e: e: e:

OC' .2 00 .. ..00

E. .. N C"

O ,i:

"C ~ . . I I I I I , I I I . I II

i1

,I

iIi . I I I : N..NN ..NN..N i i I I I . . .

:. .

.i . . I . . I I I . I . , I , I I I I ,

O ~O

5. . . . . .000r- vOOOCO i:'Òi:'Òi: 'Ò'Ò'Òi:'Ò i:'Òi:i:ci- 't't't't't 'tOOooN ocooenC"

ID ~le: e: e: e: e: e: . . . . . . . . . ¿¿¿¿¿ ¿¿¿¿¿ ¿¿¿¿¿C"IOIOO .q..i-i-o

Ol ..N.. .q

1:.2 . .

I I I I Ii i i

iI

iI

iiia I..NNN N....NN i ....NN.. i i:i i I

~

"t .§

'000.. NgOOOl . . . . . ""00 O C" . . . . . . . . . .'ti-0""C" N OCON 't't't't't ..vONv 't't't't't 't't't'tae: . . . . . . . . . e: e: e: e: e: . . . . . e: e: e: e: e: e: e: e: e: e:

.. .2I.~COO C".qmCOO inOl~OOO .

E. .. N "',i:o'f T'T''rT'T' NT'T'NN T"T'C'T'T' i ..NNN N..N.... i

I I I I:i i

~

È .!oogooo Nog0"" C"0gOOl i:0gOOl OOOOOC" i:i:i:i:ciC"oo ..C" C"C" COC" OC" C"C" .v 0lC" ootOOC"v . . . . .

ig g¡ ..còi-CÒO MCÒMCÒO ..CÒIÒCÒO e:CÒNi-o NolOolO e: e: e: e: e:

oc i: .q in C" ~ en"" ...q C"1/ lß+ 1/ lß+ 1/ lß+ 1/ lß+ 1/ lß+ 1/ lß+

ilßl~e ilßI~e ilßI~e ilßl~e ilßl~e ilßI~~1 0(, 1.8 O (, 1.8 O (, l O (, ~ 0(, -s.8 0(,~ O E gi~ ~ O E gi~ ~ O E gi~ ~ E gi~ ~ g E gi~ ~ g E gi~~~ e E E ~~ e E E ~~ e E E ~~ e E E ~~ e E E ~~ e E E(I~=~~ (I~=~~ (I~=~~ (I~=~~ (I~=~~ (I~=~~

i::f~ .. N C" .q in tO

a.

.;(1:ct!

SECTION 9

IlO

¿~:i£ClE. S

I ~ ~~ ~ i

I¡ .~~ .S!g i; :É

.! 'õ ,g

~~ 1.' :.:

(1

~Cf

5781