Document nmY29rdgJ9BML8r5wnJ3v47LR
*
Sf
{ |
A
International Research and Development Corporation
249% 1
sPoNSOR: conpouND: susJECT:
3M Company R-3022 TNoixnteeclyeyDayStuSduyb.acute Rhesus Monkey
hn
SVidcweinPrI.esiGdoblndcancahnadl, Ph.D Director df Research
Collaborators:
i
D.DiC.reJcetsosrupo,f PRhe.sDe.a,rchAssociate
-
}
R.anGd. DGierile,ctoDr.V.oXf.,PatVhiocelogPyresident
;
J. ofS. LaNreghreinAgn,imaPlh.DT.o,xicDoilroegcytor T. M. Saulog, D.V.X., X.5.,
i
Staff Pachologist
Date: __ January 16, 1979
i
137-088
\
601449
vo
International Research and Development Corporation
TABLE OF CONTENTS
}
Page FU 1
BE
3
(
III. Clinfcal Studies . uv vv vv vv vv vv vo ov a a aus
4
A MEEROd + eee. 4
i
1. General Procedure . + + + + + 4 4 toa 4 soa au
4
2. CompoundAdministration + . ss. +o... ao. 4
;
3. ObSETVAELONS + sue e au aaaanaaaa. 5
4. ClintcalLaboratory Test + + vos osetia. 5
|
ab.l HBeimoacthoelmoigsytryi + saLvLe.taia.aieiaiaa.a..ials 55
4.. stUaritniasltyisceasl +analiys.is u. .i.a.i..i.i.a.a..i.u.s. &5
Bo BeSUIES + vt aah aaa. 6
1. General Behavior, Appearance and Survival . .... 6
2. Body Weights + uv h a aiae aaa T
3. Laboratory Tests... s+ aa.a.i...... 8
!
IV. Pathology Studies + oo v4 ts ub tbe e aaa
9
AL MeEhOds uae e aaa
9
,
1. GrossPathology + + + vest esata. 9
2. HSEOPAEMOloy + + + + a aha ee uua es 9
Bo ReSUIES 4h tiiiaaaaiaae aaa... 10
1. Gross Pahology andOrgenWeights +... ..... 10
i
2. Histo+ p +va vet veh saoanlutoagaay. 10
fis
TableNo.
1. Individual and Group Yea Body Wefghes . . . . . . ... 12-13
2-4. Individual Hematological Values + + + ov oo s oo. 16-16
5-7. Individual Biochemical Values + + ov +s... 1-19
8-10. Individual Urinalysis + + vo oo vo so 0 oo 0 a 0 so
20-22
11. Necropsy Observation + usta eet. aaaa. 23
|
12. Absolute and Relative Organ Weights . . . . . . .... 26-25
13. Microscopic Observations . + o + + + oo + os oo
26-31
{| 137-088 001450
3
International Research and Development Corporation
j
rage 1
!
I. smioestsFi4-3422 was adainistered to rhesus monkeys by gavage ac dosage
|
levels of 1, 3, 10 or 30 mg/kg/day. A control group received the
vehicle, propylene glycol. Tio male aad two female monkeys were ini-
tiated at each dosage level and also in the control group. The
monkeys were observed twice daily for general physical appearance,
|
behavior and pharmacotoxic signs. Body weighs were recorded weekly.
Hematological, biochemical and urinalysis studies were conducted once
i
in the control period and at 1 and 3 months of study.
i
One monkey treated with 30 mg/kg/day died during the last week
of the scudy.
On and after the second day of study, all the monkeys,
fncluding the control group shoved anorexia, slight to marked decrease
|
in activity and ataxia. The ataxia disappeared from all the monkeys
directly afcer the amount of propylene glycol used vas reduced from 5
to 2 al/kg on study day 3. Occasional emesis and diarrhea (sometimes
!
severe) were observed. Several weeks after the initiation of the study
|
black stool, mucus and bloody mucus in the stool were observed in most
of the monkeys from each group. For two monkeys receiving 30 mg/kg/day
the above mentioned signs of toxiciey persisted for alsost all the
!
treatment period. One monkey at the 30 mg/kg/day dosage level died
during the last veck of the study.
Most of the monkeys, including those in the control group lost
body weight early fa the study. At 12 weeks of study all the monkeys
were at or mear the original body weight except for the groups
receiving 10 and 30 mg/kg/day. At the end of the study the diifereaces
in the mean body weights of the treated and control groups were mot scattscically significant.
137-088
001451
.
International Research and Development Corporation
|
Page 2
Microscopically, the adrenals from one male and two female rhesus
monkeys at the 30 mg/kg/day dosage level had compound-related slight
to severe lipid depletion. The pancreas from the tuo female monkeys
at the 30 mg/kg/day dosage level had compound-related moderate atrophy
of exocrine cells. Nome of the tissues from the other monkeys had
lesions that would be considered compound-related.
)
Statistically significant variations in sex group mean weights
of liver and brain occurred between the control and experimental groups.
:
These variations were of unknown biological significance and were mot
i
accompanied by morphologic alterations.
| |
|
137-088
00145,
!
International Research and Development Corporation
i
Page 3
|
1m. coon
The compound vas received from 3M Company, Saint Paul, Minnesota
{
on October 28, 1977 as indicated below:
Label
Description
FN-3022 61-2700-3422-0 Lot 784/Net-35 DR-1
off-white to tan waxy substance
1
ii
137-088
001453
International Research and Development Corporation
|
Page 4
III. CLINICAL STUDIES
A. METHOD:
|
1. General Procedure:
|
Ten male (veighing from 3.00 to 4.35 kg) and 10 female
i
(weighing from 3.05 to 4.20 kg) rhesus monkeys were initiated {nto
!
this study. The monkeys were purchased from Primate laports
\
Corporation, Port Washington, New York on October 25, 1977. The
:
monkeys were housed individually in hanging wire sesh "squeeze-type"
\
cages and maintained in a temperature-, huaidity- and light-controlled
environment. Purina Monkey Chowd was fed twice each day and fresh
apples vere fod 3 times a week. Water was available ad libitum.
\
During the conditioning period (14 weeks), the monkeys were
i
tattooed on the inner surface of the thigh and intrapalpebral tuberculin
|
tests were conducted. Tuberculin tests also were conducted at bimonthly
intervals during the treatment period. Complete physical exaainations
!
were conducted by the staff veterinarian prior to initiation of the cou
pound administration and only monkeys in good health were selected for
i
use.
i
This study vas initiated on February 9, 1978. Terminal sacrifi-
|
ces were conducted on Yay 10, 1978.
l
2. Compound Adatntstration:
|
fate 5 gArtouptsheonenda orfandtohem cbaosnidsi,tiosnointghatpertiheodavteheragmeonkbeoydsy wweerieghtdsivviedreed
statlar:
|
Group
HaNluember of MoFnekaeaylse
Dosage Level
:
1
2
2
Control
{=
m111
22
22
31 mwgg//kkgg//ddaayy
|
w
v
2
2
10 ug/kg/day
2
2
30 ag/kg/day
137-088
|
001454
:
International Research and Development Corporation
i
Page 5
The test compound was dissolved in propylene glycol by heating to approxizately 30 C. The solution vas adainistered by gavage. For study day | and 2 all of the treated monkeys received 5 ml/kg of the
solution. On and after study day 3 the amount of propylene glycol vas reduced to 2 ml/kg. The control group received 5- and then 2-al/kg of
!
propylene glycol on the same reglaen as the treated groups.
Individual daily doses were based upon the body veights
t
obtained weekly.
3. Observations:
|
The monkeys were observed twice daily for gemeral physical
appearance and behavior and phatmacotoxic signs. Individual body
weights were recorded weekly. General physical examinations were con-
ducted in the control period and monthly during the study. Food com-
sumption vas estimated.
4. Clinteal Laboratory Tests:
Blood and urine samples were obtained for analysis from all
!
monkeys once during the control period and at 1 and 3 months of study.
!
The monkeys were fasted overnight prior to the collection of blood and
|
urine samples.
a. Hematology:
|
Hematological studies included: hemoglobinl, hematocrit?
'
erythrocyte count, totald and differential leucocyte counts, reticulocy
|
count?, platelet count', prothrombin time, activated partial throm-
'
boplastin time (APTT)'. Mean corpuscular volume (MCV), mean corpuscular
i
hemoglobin (CH) and sean corpuscular hemoglobin conceatration (CHC)
i
were calculated.
|
b. Biochemistry:
Biochemical studies included: blood glucosed, blood urea
)
aitrogend, serua alkaline phosphatased, serum glutamic oxaloacetic
i
transaainase (SGOT)S, serua glutamic pyruvic transaminase (SGPT)S,
|
137-088
|
001455
:
International Research and Development Corporation
rage 6
cholesterol? total protein', albuain, sodiual, potassiuall, chloride?, inorganic phosphate?, Y-glucanyl transpeptidasell,
creatinine phosphokinasel2, Sorbitol dehydrogenase vas not detarained because reliable data could not be obtained with the present instrumentation.
c. Urinalyses:
Urinalyses fncluded: measurement of voluse, pil} and
specific gravity; description of color and appearance; qualitative
tests for protefal, glucoseld, ketonesl3, occult bloodld; and
!
atcroscopic examination of the sediment.
4. statistical Analysts:
Analysis of terminal body weights and organ weights (absolute and relative) and clinical laboratory tests vere performed using analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal and unequal variances) as described by Steel and Torrie using Dummett's multiple comparison table to judge significance of differences. 3. RESULTS:
1. General Behavior, Appearance and Survival:
Monkey 7490 receiving 30 ug/kg/day died during the last veek
{
of the study. The death was preceded by a marked loss of body weight
(1.25 kg) with a marked decrease in activity and ataxia.
]
Except for one monkey receiving 3 mg/kg/day, ataxia was
observed for all the monkeys in the control and treated groups
begianing at day 2. For most of the monkeys the ataxia vas slight but
for a few the ataxia vas moderate or marked. With the reduction in
the amount of propylene glycol use the ataxia disappeared usually
before the end of the first week.
,
In addition to the ataxia the monkeys in the control and
treated groups had anorexia, slight to moderate decreased activity
.
appearing on study day 2. Occasional emesis also was observed.
t
137-088
01456
i
International Research and Development Corporation
|
Page 7
'
For the monkeys in the control group, diarrhea was occasionally
observed but for Monkey 7470, the diarrhea uas chronic at the end of
the study. After the second week of study, bloody mucus in the stool
and black stool were noted. Except for the chronic diarrhea, the
!
observations for the monkeys
that of the controls.
receiving
1
mg/kg/day
were
the
same
as
|
At the 3 ug/kg/day dosage level Nonkey 7487 was observed to
)
have black stool and mucus in the stool during weeks 11 and 13.
i
Frequently, severe diarrhea was noted for Monkey 7474 during week 12.
For the monkeys at the 10 mg/kg/day dosage level, occasional diarrhea
was observed.
Of the monkeys receiving 30 mg/kg/day, 7499 had bloody mucus
|
in the stool, emesis and severe diarrhea from the third day of the
.
asdtuddiyt.ionSefvorereMondkieayrr7h4e9a0wmauscuosbsefrnvetdhe fosrtooMlo,nkebylsood7y472mucaunsd
7490. Ia
and blood
in
the stool also was noted. For Monkeys 7499 and 7430 the signs of
3
toxicity persisted for most of the treatment period. Monkey 7430 that
died fn the last week of the study showed marked decrease ia activity
and marked ataxia on the day prior to death.
|
2. Body Weights (Table 1):
:
During the first month of study, all the monkeys lost weight
!
including those ia the concrol group. The percentage change in mean
-
body weight, at monthly intervals were:
i
HSetcudkye
=
---- pa Group, dose in pC mg/kg/day
pa
!i
p0u-4 "Eire SWa0l2z9 w0i.s29 "EEls
3T0ok
12
+16
2087
+09
0.60
3s
For the group receiving 30 mg/kg/day the low mean body weight
resulted mainly from the 1.25 kg loss in body weight for Monkey 7450,
137-088
i
601457
i
!
International Research and Development Corporation
|
rage 8
{
which died. Hovever, there were no statistically sigaificant dif-
ferences between the body weights of the treated and control monkeys.
3. Laboratory Tests (Tables 2-10):
After the first month of treatment no unusual changes were
i
observed for the blood and urine analyses. For Monkey 7491, receiving
!
10 mg/kg/day, there vas a slight decrease in hematocrit, hemoglobin
i
concentration and erythrocyte couat at 1 month of study as compared to
{
the precreatment period. This decrease was not found at 3 months of
study.
!
For most of the monkeys at 3 months of study, the blood glu-
cose values were in the lower range of expected values. Also at 3
i
months of study, low cholesterol values (56 and 67 mg/100 ul) were
found for two monkeys receiving 30 ug/kg/day, and for one monkey
i
receiving 10 mg/kg/day (84 g/100 ml). For Monkey 7477 which had a
cholesterol value of 67 ag/100 al, a low potassium value (3.5
i
meq/1iter) was found also.
il
|
|
|
i |
|
137-088
|
01458
International Research and Development Corporation
i
Page 9
IV. PATHOLOGICAL STUDIES
i
A. METHODS:
1. Gross Pathology:
After completion of the compound administration period all surviving monkeys vere anesthetized with Sernylan, exsanguinated
;
and necropsted. At necropsy the heart, liver, adrenals, spleen,
pituitary, kidneys, testes/ovaries and brain were weighed and repre-
i
sentative tissues vere collected fa buffered neutral 10% formalin.
by
Eyes were fixed in Russell's fixative. The thyroid/parathyroid was
|
weighed after fixation.
The monkey which died during the study was necropsied as
above.
2. Histopathology:
||
Microscopic examination of formalin fixed hematoxylin and eosin stained paraffin sections was performed for all monkeys in the
control and treatment groups. The following tissues were examined:
i
adrenals
aorta
kidneys Liver
pliutsubiatrarsypinal cord
|
bone
lung
stomach
|
besroapihnagus
sgkeisnenteric lymph node ttheysrcoeisd/ovaries
|
geaylelsbladder
rentordoepharyngeal lymph pSahrymautshyroid
|
hevaerstse(lwsi)th coronary nmearmvmeary(wgiltahndmuscle)
duodenua
spleen
ecornascihlea tongue
|
ileun
jejunum
pancreas prostate/uterus
urinary vagina
bladder
Suge
}
colon
ibnarjruonwc)tion (bone tattoo
i
rectun
salivary gland
|
and any other tissue(s) with lesions.
#Phencyclidine KCl - BioCeutic St. Joseph, Missouri.
Laboratories,
Inc.
137-088
{
01459
International Research and Development Corporation
|
Page 10
:
B. RESULTS:
|
1. Gross Pathology (Table 11) and Organ Weights (Table 12):
No gross lesions considered coupound-related were seen in monkeys
|
sacrificed after 90 days of study.
Statiseically significant variations in sex group mean weights of
i
Liver and brain occurred at the 10 and 30 mg/kg/day dosage levels as
'
follows:
i|
organ D(omsga/gkeg/dLaeyv)el Sex Weight
Change
<
|
Liver 10 30
u M
absorleultaet,irveelative increianscer,eianscerease 00..0055,0.01
Brain 3100
uu aabbssoolluuttee
ddeeccrreeaassee 00..0051
The biological significance of these organ weight variations is not known.
|
These organ weight variations were not accompanied by morphologic changes
which were considered compound-related.
2. Histopathology (Table 13):
|
One ale and two female monkeys at the 30 ug/kg/day dosage level,
sacrificed after 90 days of stuly, had slight to severe lipid depletion
!
in the adrenal glands. The two female monkeys at the 30 ug/kg/day dosage level had moderate atrophy of pancreatic exocrine cells. The lesion was
! t
characterized by decreased cell size with loss of zymogen granules. One of the two pancreas also had several eosinophilic intranuclear inclusions
|
in exocrine cells. These microscopic findings were considered compound-
!
relatNeod.microscopic changes which were considered compound-related were
|
seen in the adrenal glands of sale or femsle monkeys ac the 1, 3 or 10
wg/kg/day levels. No microscopic changes which were considered compound-
|
related were seen in the pancreas of male monkeys at the 30 mg/kg/day
Jevel or in male or female monkeys at the 1, 3 or 10 mg/kg/day levels. Wo
}
microscopic lesions in tissues other than the adrenal glands and pancreas
!
of monkeys at the 30 mg/kg/day levels vere considered compound-related.
137-088
3
601460
International Research and Development Corporation
Page 11
References
1. Coulter Hemoglobinometer, Coulter Electronics, 590 W. 20th Street,
Hialeah, Florida.
2. Microhematocrit, John B. Male, 3rd Ed., 1967, The C. V. Mosby Company
p. L156.
3. 5C9o0ulWt.er20PcahrtiSctlreeetS,izeHiaCloeuanht,er,FloMroiddeal. Zg, Coulter Electronics,
4. RGeriatdnuahno,l'sEdiCtloirnsica6lthLaEbd.o,rat1o96r3y,MeTthheodCs.V.andMoDsibaygnCoosmipsa,ny,Frap.mke1l132a.nd
.
5.
Coulter Particle Size Counter, Yodel A, Coulter Electronics, 590 W. 20th St., Hialeah, Florida.
6. General Diagnostics - Warner Chilcott Laboratories, Revised April 1965.
7. General Diagnostics - Warner Chilcott Laboratories, Revised Jaauary 1967.
8. Technicon Auto Analyzer 6/60 Micro Methodology.
9. Micro Auto Analyzer II, 6/60 Micro Methodology:
10. Atomic Absorption IL Model 353.
|
11. Glutasyl transpeptidase, Signa GGT, Bulletin 545.
{
12. Creatinine phosphokinase - Sigma Procedure Bulletin 520.
137-088
i
601461
WM 300 3.00 3.25 305 305 3.05 30s 3.20 325 330 3.0 320 325 3.35 300k
WHoys FF303705 338003 33000 337000 2386s0 32385 32.5600 336000 33.0005 30000 23.3600 228905 33.0600 33.8055 L2o7s Hoan, 336 355 1 055 348 LAL BAL 343 05 34s 3 43 341 oss a LE spligM fany: 38 400 N75 395 305 385 83 395 335 400 395 400 405 4d 3a WW um 3 330 32 300 do 300 Nm 320 303 0 300 325 30 290k oSeM m F 3w0n5s a3.o05 2d9s5s 33.7050 239600 33.030 33035 33305 36.20 165 I6s0 3025 33.6200 331550 3a.1s06 Bo vem 335 336 346 349 33 DI 03 S46 10 349 345 346 35 As 8 desis: BeWsa MM0s1s0 43000 4s0l5s G30505 33.5935 63.0505 630650 0570s 431005 431730 43000 L3I8S0 G4I0S0 43200 4s1e0ek W Wer rra3s60 33205 33sm 5330 33330 000s 334200 31m0 5150 13500 d0ds A2ss 235050 230 ddooes Mean 355 BSL BS 3S AS 050 05 2.61 68 2.66 236 26 70 0 3s
157-088
"Tern wetghe.
z
mez
TLE 1. cont.
MGornokuep,y
contest
ember sx T1o0
10safuany: WTIBS WWo 28da0s 3L3E0 MWOaL PP4300 430055 wean 36 355 30 mp/iglany: WWTR MM324530 334505 S Sd m PF36000 432005 3 Mean 349 355 &
Hinecy Day Subacute Rhesus Nonkey Toxicity Study. Individual and Group Mean Body Velghs, Kilograns. I 7 3% 5% eek1 of Stu8dy 5
33600 33550 333400 335205 334355 3d4os 3d6ds0 L2I4Ss 2U00 32.3600 336005 32.9350 239550 33.0500 2L9A5S 4300 2240s0 323950 208 343 3 330 33 33 339 336 326 332050 33200 B3I5S0 B3.A6S0 33265s 33265s 370s0 233705 337355 32.76s5 32.9655 323850 325900 32.06955 32.8555 23..6050 126900 22.5805 319 33 325 3 33 LB 34 339 LM
Wm
335500 23.6500 d30s5 233005 238 136 13300 332505 329s0 2218S0 29 228
m1
3357s5 dIamsee 22.0200 32..095 33 32 342050 2s.0e% 22.09855 26.85 02 is
131-088
ASTeexcaatinoaall wveeligghht.not Included tn mean.
z
ny
PE a WH
pe.
be te aPrato osteo ote bor bares wo
en Em whe OFT dhe TE SE Op
op
me"
ea
Leatons
S SmeeniT mn eEm}N omm um aowmoeewoomnoomn oonw ore owmoarrsoanonwm
Bg oomWeoeraoammo omwa 3J
3wo
omomoowme oMemoon
s x wwoarnwoora na oon aounow
2 en
fryer
}
x
fn oe wee eteathinoitee miterniRe hae
ReHT IRN YW SL ET aa mn Se op AR ai yee
----
EE
i.
:
Wome wu ea ono
gF o MmE R pR m Bs
OED ROWE OW
:
oR ETA A A A A
mow on worn ort uwo
G Bm n em me ow om om om
om mos 0
A ma 4 a mom
=
A
J E L ET gm Nm EmnEeeN Sh SFRRRTwWiRNham,
1 malrghioy:
.
3 mihglinys
-
ggeo
Wmoiim Lon
M1 og RI
iE: moEm LhobEE oEhRE hT:
|
BEORoEBoELIEoLLsIEpIRnLE
wo
rm
wm, Feu Bow we BF om wm opy TF ome me vie mone
nan a p MIE mW OT T mm WE wagon ggw :uwmm sor owmom3 ouw;awog 2 oma wee
A2 roof
E mEua n Bu we BE gFmedre TE eo fp ie poe
A mihi:
.
}
2) mshgtiny:
-
BF OELmE op E ULmY LaLw LmEoEmDEo E oowm moE e dpmE o sEtnaRnowEnaEEn "5w: B OwM irammommsom oonn ooms momoomiom ooswmommomoomepmomomonoon y
malay:
-
}
}
-
`
Em rhe ew Faryrives Foes
A meShgliny:
-
-
wtiction:
}
Q Woovonomn mow amo
om
onomon
3
:
B S e on wma mw " ae mm ar ms 51
.
freer
"
}
Bor Fen Wow BN 5 WUT Bowe WLW
nin
2 mhgfiar:
Wo
El
))
E EEI
FEET. BEAT LE, TEE
:
So
EE]
" :
o-
Lo
:
tun
Cay nem ow
." . :
: oo
Lo
u
Tut
we rs rem ow
" : -
:
=v
-
:
a EE EE g Em oyonouamom or
Pro
= 3rR
eww ase e2 Len wweeoyomoowaeme 3wm doeems ox
:: : ": -
. -
<: -'
LE
:
Ife
ie mo Lew ow " - - " :
Domo
AL maliglinr:
.
:
2mhlders
:
.
:
' or
oS Ba tomer mDommo o) oorro orowowororo c: Ln: sor : r or
BBOEaow mmo oor
apc
Bomonogomamoamororoxopoo
ow py
ome
EEL
&
Page 23
mess
I
----
:
TABLE UL
Necropsy Observations.
cote Lite afar Safer sda
sizTeerisn
$s:34855858% 335RE3F% $BE2E3F3 f5E3F3E% B5E3G3Gi
een tiem
<x
.
.
| tras stes chromentat, sestassnnty
fTyrLf aliiiotve-r ernasds-gray foct (site lesions) :x ttee enie emrtases, ov
| strenetpcaenotaaersteteslerr, smevscery x x "pBSaHrerAtA eTsot spobser E erate seSpL omsaonR ul s nS ota
, TIhemnn
!
|
SeeaEellaAttEatarehsssi.sne , sie entice
Shia
os
i
=.=
xx
::= x
. .
.
.
en 3
FI
xx
. .
SC . .
. . :
rn 001473
ave ty a opm po, rh ies ro,"
o
EE
a
EE Emme pete em eee a
flaw
i
ne
har
a S o g m w m--
3
a
TOWoMSam kwem D Too mamnbem
Bmmomam RmRm aw na
} o am mam wmoaoaw no
} wwmhoeme noamn eowe Bowe
wmoemm ammoomn wn em
mati
Einar
ai
-
or
eyht ur te 7 i te TR CH
y
i
i ws,
v=r,
T-TT TTTgyT.T|T Sw yr gee. o peeT p,
10 mihi
:
}
1.0 melhor:
"
-
"
}
g2 os Mm
: '
=1-
EVNoaR wtan
Wwuammo eimm
uwmnmam ER ie
meeomem im im
a
:
-
hea uno
mh
moa
# 1.0 slater
-
'}
0.0 wring:
Fin
'
-
;
i
_ Sane up spans onan ney Sete dent Page 26
mm mare ewer Gamer Bates
rime
Hissesssssasassasssnis
i 00 "Ltt
EL ercmpstes spins
| armea s : i
focus of lyaphotd tafilsrace
rr i tt
i EE pgs ar .
!
Adrenal
anil fact of iraphotd
ry
!
tadiridual to small groups
t
1
'
Jeopeta
3
e3peta and cosa
2 303 2
.
pag
ons
}
;
3: :
[
1
ro
1
t
)
2
32
2
jie =
2
2
1
32 3
1
001476
Page 27
fn ieou
ooeem rm
i
Sines oyA dSiuesssceueenerTohewsSsecNsoisdeosonTnosti Scr. eee
_Cosczo|l Lsa/xg/dav Jawad 1a0mkaidey 330aluadar
| ame
i ute
id $BiiE2T2H3XI%F R B3T R5E 283x R: R3TR5AR3X%I; R$fEIE3I%XLRr R53Ex 83Z
See "idastan pigeenc GENIN (perideancatal, saa: pai: 2103 a2: saad
:
fTroioitdrtngreeacsres pa tseoatolar TIA
ss pass2
s:a sas r: rs ia ai1Ha id
E eE SraL nl la aenneset yn >
soes Le
.3 >
eTiJnvrer--n--e
v 3
T
Tt
5 T
STTArTaIatvH eeTs oi fTEtmce araTcrieaAtatnLe
dias o1 eeegress
x1 o2ria gtgeesesesemge
em1g33
S --Siimff A conpscion
Ti Tia
EiiTiiCii:
aiiiiiS TriiiriE riiiasn
>
|
TeTBsEe eusuiens Bio
seston
To
aii
fr . ii:
=
.
hn
>
i
5:
= iii:iii: x1c Tien ain
--
i ir
| L SSirElE iaiAenHaLmeI sees tweren
:
:
STFS porii e in amn StsmsDuEe a" - x
i
:
tas
ESLm aaTaEnLT AT RRL S
5
| SSEaTaiianntmpraovens wicsohnostetleer sar: ox aa
|i 2EC 0 WUinR LesRdepeS nemsctosntaoteae 33 3333
Sot
sr
ITSnIrnEoma
aiiaosiz:
:
333
FSI eIESIhnEra
oa3an vad)
|
601477
| mrEeeEn !
TABLE 13. Cane.
rage 26 SoewygfyaoSmAeESs eng BE Ss
r-- E rrr Miczoscopic Observacions.
_Senczel Lag/ke/dav )salka/dav 1s0u/kaidav JaOefiaidav
nme=
(j3f 2323525: 3FE28i3 F3I2F3O3 5F33I2I3E os33a3a:
T rTye _--_--T
-- sass aa 1 aaa
33a
= iaas
TTErES i
E sumremrS acit
il i Se
sis TT ror T rr rrr: ras
ss
: ero:
.
a BS ea a, E
3 5
p a EE AAL T fociof inflammatory call
3
24
ss
2
sas
333
3 33
.
AWELT2EaEmt]
ies eens
3s
Ee
| D2OaRE ni
:
gon
;
| Tamm
TTT TTT iT aa
I =Tans pn i sm, TTT .. TT
.1
IJJIeEEl eTSe R1+r iveiros I
..
.
ss
| LpT iaEo sn
.3
i
! ran
ge pbfrooomi m?pnalll Prli2hzme,ne e
|
601478
Page-29
i mfeewas Taz 1. cone.
eSiawacyesay Seubueeaca heaems donkey Toxiescy ssn. Scents Saaacions
:feedee
Sion seem pessalons 12
rel Lawes awe 10st 30 sued
sffSiiiEisssxzgM5s3Ey3R X33R5sR5e%yROK33$R3$8E3%%S FsSR$EAEsfNy S3Ag5Aiit3R
1
Ti
rr 1
|
02nr8eirlooirrcsrbasacaedmsasec8soeenmcayaccayciaactts,
5
3s
tcootlptt oaftrsinnefdliaammtmaattoorreyy fcaariltl
1a
3
oelierican a soscataris
2 >
tI olSaitreanasrae1pmacseaesrcrioFiarmisesamnstsiderta
5
>
|
smiotrhltTschacen5isa seconhemorenase :
3
2
:
pr Toooktioifcitaacteinamfaacomrbyeaaitartts
Ti 32
1
13
iii
11.1a:iv
ssoodfarSiriHclieneRdtuapIetmaenrtaaitiperospiiamacte 33 3
|
foSrime i sesenconp n h
>
Tomparrroigune panies
Tri: te
Tit
TT
i
otodSialrpmismenetrsialTaLrospshasd heir
3
1
>
5
3
TRearalralmtfi ieryvatculatesdttiences
33 60 se
1333
136 21 4 3332 3
||
Speirrieistrpontof
<ilfan persion
sia sr: oa 3 3a: rii
SsS eEeLETaIranN MseamSs 3m4EainmS iaon pha: 2a: 2:2 ra oan :
|
sal capesiar fisrosts
3
eHaat pE urenchyae altiscan sts oe
:
Coie:
xFe INmeiEpeeteen prreassne
- dees ila
wren
SIG
Itahe
!
601479
rage 30
R ---- ie e tr eme aBne eSeo iste s Sn een
TE 5
iets
reuRamme
i$283)81.82E22E52F5 5F33E3E3 3T :eE3aY3s $cSi3Es3E: B3s3aEi:s:
emer
iis
wlSethmeerraBicieesitaattanaikhepeporpopeesss
sae
>
:
ra ss :
s
i ,
wPS elirllcia ytBeahsma1hyrtaeacsuproves, s
ss
ss
Sats meee
s
; awluTTrrtaoees A elmiet. nesses
T Tar: aaa ars 12: 11a
SaShHieRriI. sine :
io
:
2:3
sco shim Setar apelin
s
||1 CpeLot iSeines rvs
To se :
RAEI, ut seen
sana: iia
wfC EEREb LE, 3
i
2
>
>
is
i
FBe5lliSRsehsesAisarsTiomensws seen .s
xs
xx >
x s
.
atl TE arcremnte
i OvahTrtEaas et of ercropntc atmamisascion 11
x1
.1
FE
1.
i HEeLiterete temness ss is fi
ss s
|| Flaioenn
5
-137-283
.
t
PF SIraivinimeamee .
i SimimEla.
a = aucalyzed
600114d50
I.
raga
Dseesmme | mEeEeEn oe
vSieseucrrouuydsSSeeuaaatssrcaueetceeeBamasiensousaswSersoshsenysSsmiestsiSufir
Gms Liye lanes Dower 0 suwer
Sant
Lom Lorin
101s:
S(d3H RBREERF
acs:
ORERSEY
si3:
RSRFERE
23:2
RGREERR
53k:
GzRiCt
pm ot spent mts
Tr
I
T
Tr
qi
LovSieotksstieprhiadaeseschzotnadl suctaasceta Sopris imi searise sands
3 so
|( --1--5p2 aofptrimprose mtnicraces --
faint prance
se
se
--
3a
I
ie
' PSrs eigiorR
is
>
i:
2:
In
Septem wuncie
Tia
tii a
Tie
E SeiT te E men
1122
se
:
i
sp rmpLenuriiar Grnafcasnmii sscov m sale i aftta
2232
.
3 32:
53.
123 3 21133
53sxx 53xx
11
x3
y sEI eeeEsIa. s edemrmias meron
3 sx sas: sxxx xxx:. sess
i
fSHriiEenisRctiAas cat tetssemaces
33
saa s
s
2
3
5
|= =
iii iid iii: tia tii Toil iii ii iiair: oi
{|
!i ies
ta xfpebrocosnnytptmsetmeineorPuase 4[pat= midesye
Son
Rie
60isud