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x
e
n
o
bi
o
t
i
c
s
)
i
s
t
h
e
b
e
g
i
nn
i
ng
o
f
t
h
e
da
m
a
ge
t
o
t
h
e
b
o
d
y
'
s
de
f
e
n
c
e
s
y
s
t
e
m
a
ga
i
ns
t
pa
t
h
o
ge
ns
[
7
-
8]
.
On
e
c
o
m
po
n
e
n
t
o
f
t
h
e
c
e
ll
u
l
a
r
im
m
u
n
e
s
y
s
t
e
m
t
h
a
t
pl
a
y
s
a
vi
t
a
l
r
o
l
e
t
o
r
e
gul
a
t
e
t
h
e
im
m
u
n
e
r
e
s
po
ns
e
due
t
o
e
x
po
s
ur
e
to
i
m
m
u
n
o
s
uppr
e
s
s
o
r
c
a
r
c
i
n
o
ge
ns
i
s
C
D4
T
h
e
l
p
e
r
(
T
h
)
a
n
d
T
r
e
gul
a
t
or
y
c
e
ll
s
(
T
r
e
g)
[
8
]
.
As
a
r
e
gu
l
a
to
r
o
f
t
h
e
a
d
a
pt
i
v
e
im
m
u
n
e
r
e
s
po
n
s
e
,
T
h
e
l
pe
r
lym
p
h
o
c
y
t
e
s
p
l
a
y
a
n
e
s
s
e
n
t
i
a
l
r
o
l
e
i
n
i
d
e
n
t
i
f
yi
ng
a
n
d
r
e
s
i
s
t
i
n
g
t
h
e
de
v
e
l
o
p
m
e
n
t
o
f
pa
t
h
o
ge
ns
o
r
n
e
o
pl
a
s
m
s
i
n
t
h
e
b
o
d
y
.
W
e
a
k
po
s
i
t
i
ve
im
m
u
ne
r
e
a
c
t
i
o
ns
,
pa
r
t
i
c
u
l
a
r
l
y
c
e
ll
u
l
a
r
im
m
u
n
e
r
e
s
po
n
s
e
s
,
t
o
pa
t
h
oge
ns
i
nc
r
e
a
s
e
t
h
e
o
r
ga
ni
s
m
m
o
r
bi
d
i
t
y
a
n
d
m
o
r
ta
l
i
t
y
[
9]
.
T
h
e
l
pe
r
c
e
ll
s
p
l
a
y
a
r
o
l
e
i
n
de
s
i
g
ni
n
g
c
e
ll
-
s
pe
c
i
f
i
c
i
mm
u
n
e
r
e
s
po
ns
e
s
,
w
h
e
r
e
a
s
T
r
e
gu
l
a
t
o
r
pl
a
y
s
a
r
o
l
e
in
r
e
gu
l
a
t
i
n
g
t
o
l
e
r
a
n
c
e
r
e
s
p
o
n
s
e
t
o
p
r
e
v
e
n
t
e
x
c
e
s
s
i
ve
im
m
u
ne
r
e
a
c
t
i
o
n
s
[
10]
.
B
e
c
a
us
e
e
f
f
e
c
t
i
v
e
c
a
n
c
e
r
t
h
e
r
a
pe
ut
i
c
m
e
t
h
o
ds
h
a
v
e
n
o
t
b
e
e
n
f
o
un
d,
t
h
e
s
e
a
r
c
h
c
o
n
t
i
n
ue
s
t
o
f
i
n
d
c
h
e
m
o
pr
e
v
e
n
t
i
v
e
c
o
m
po
un
ds
t
h
a
t
c
a
n
b
e
u
s
e
d
t
o
i
nhi
b
i
t
o
r
de
l
a
y
c
a
r
c
i
n
o
ge
n
e
s
i
s
due
t
o
DM
B
A
e
x
po
s
ur
e
.
An
t
i
o
xi
da
n
t
s
,
pr
o
a
p
o
p
to
s
i
s
a
ge
n
t
s
o
r
a
n
t
i
-
pr
o
l
if
e
r
a
t
i
v
e
a
ge
n
t
s
,
a
n
d
i
mm
u
n
o
m
o
du
l
a
t
i
o
n
a
r
e
t
h
o
ugh
t
to
i
m
pe
de
c
a
r
c
i
n
o
ge
ne
s
i
s
o
r
pr
e
v
e
n
t
ne
o
pl
a
s
m
f
o
r
m
a
t
i
o
n
[
11
-
12]
.
A
n
t
i
o
xi
da
n
t
s
p
l
a
y
a
r
o
l
e
i
n
i
nhi
b
i
t
i
n
g
t
h
e
f
o
r
m
a
t
i
o
n
o
f
DM
B
A
-
DE
[
13
-
14]
.
A
n
t
i
o
xi
da
n
t
s
p
l
a
y
a
r
o
l
e
i
n
i
nh
i
b
i
t
i
n
g
t
h
e
f
o
r
m
a
t
i
o
n
o
f
r
e
a
c
t
i
v
e
m
e
t
a
b
o
l
i
t
e
s
DM
B
A
-
DE
s
o
a
s
n
o
t
to
b
e
c
a
r
c
i
n
o
ge
ni
c
,
h
e
pa
t
oto
xi
c
o
r
i
mm
u
n
o
s
uppr
e
s
s
i
ve
.
On
e
o
f
th
e
p
l
a
n
t
s
e
m
p
i
r
i
c
a
l
ly
a
l
r
e
a
d
y
us
e
d
a
s
a
n
o
xi
da
t
i
v
e
c
h
e
m
o
pr
e
v
e
n
t
i
v
e
a
n
d
im
m
u
n
o
m
o
du
l
a
t
i
o
n
i
s
bl
a
c
k
c
u
m
i
n
s
e
e
d
o
r
Ni
ge
ll
a
s
a
t
i
va
(
S
a
t
i
v
a
)
.
T
h
e
c
o
n
t
e
n
t
o
f
bl
a
c
k
c
u
m
i
n
s
e
e
ds
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t
hym
o
qu
i
n
o
n
e
,
i
s
pr
o
v
e
n
l
a
b
o
r
a
tor
i
c
a
l
ly
a
s
im
m
u
n
o
m
o
du
l
a
t
i
o
n
b
e
c
a
us
e
i
t
c
a
n
i
nc
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e
a
s
e
c
e
l
l
u
l
a
r
a
n
d
h
u
m
o
r
a
l
i
mm
u
n
e
r
e
s
po
n
s
e
.
E
t
h
a
n
o
l
e
x
t
r
a
c
t
o
f
bl
a
c
k
c
u
mi
n
s
e
e
d
s
c
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n
i
nc
r
e
a
s
e
t
h
e
a
c
t
i
vi
t
y
o
f
ph
a
go
c
y
t
o
s
i
s
a
n
d
m
i
c
r
o
bi
c
i
da
l
m
a
c
r
o
ph
a
ge
s
[
15
–
17]
.
B
l
a
c
k
c
u
mi
n
s
e
e
d
o
i
l
(
B
C
S
O)
i
s
t
h
o
ugh
t
to
i
nc
r
e
a
s
e
h
e
l
pe
r
T
c
e
l
l
f
u
n
c
t
i
o
n
a
n
d
a
f
f
e
c
t
T
r
e
gul
a
t
or
,
b
u
t
u
n
t
i
l
n
o
w
t
h
e
r
e
h
a
s
b
e
e
n
n
o
r
e
s
e
a
r
c
h
o
n
t
h
e
e
f
f
e
c
t
of
B
C
S
O
o
n
t
h
e
n
u
m
be
r
a
n
d
a
c
t
i
vi
t
y
o
f
T
h
a
n
d
T
r
e
g
l
ym
p
h
o
c
y
t
e
s
i
n
DM
B
A
-
i
n
duc
e
d
S
pr
a
gue
-
Da
w
l
e
y
(
S
D)
r
a
ts
.
2.
RE
S
E
AR
CH
M
E
T
HO
D
2.
1
.
De
s
ign
T
h
e
s
t
ud
y
us
e
d
a
r
a
n
do
m
i
z
e
d,
e
x
pe
r
im
e
n
t
a
l
de
s
ign
w
i
t
h
t
h
e
c
o
n
t
r
o
l
gr
o
up
i
n
96
f
e
m
a
l
e
S
D
r
a
t
s
.
B
a
s
e
d
o
n
t
he
r
e
s
u
l
t
s
o
f
pr
e
vi
o
us
s
t
ud
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e
s
i
t
i
s
k
no
wn
t
h
a
t
t
h
e
i
m
p
a
c
t
o
f
DM
B
A
e
x
po
s
ur
e
i
s
i
nf
l
u
e
n
c
e
d
b
y
ge
n
de
r
[
18]
h
e
n
c
e
t
e
s
t
a
ni
m
a
l
s
a
r
e
u
ni
nf
o
r
m
e
d
by
f
e
m
a
l
e
s
f
o
r
r
e
a
s
o
n
s
to
r
e
duc
e
ge
n
de
r
bi
a
s
due
to
e
n
do
c
r
i
n
e
f
a
c
t
o
r
s
.
T
hi
s
r
e
s
e
a
r
c
h
pr
oto
c
o
l
h
a
s
o
b
t
a
i
ne
d
e
t
hi
c
a
l
c
l
e
a
r
a
n
c
e
(
No
043/K
E
C
-
L
P
P
T
/I
I
/2012)
f
r
o
m
a
r
e
s
e
a
r
c
h
e
t
hi
c
s
c
o
m
mi
t
t
e
e
f
r
o
m
Ga
d
j
a
h
M
a
da
U
ni
ve
r
s
i
t
y
(
U
GM
)
,
Y
o
gy
a
ka
r
t
a
,
I
n
do
n
e
s
i
a
.
2.
2.
M
at
e
r
ial
s
an
d
r
e
ag
e
n
t
s
T
h
e
m
a
t
e
r
i
a
l
us
e
d
i
n
t
hi
s
r
e
s
e
a
r
c
h
i
s
bl
a
c
k
c
u
m
i
n
s
e
e
d
o
i
l
pr
o
duc
e
d
i
n
t
h
e
l
a
b
o
r
a
to
r
y
o
f
P
h
a
r
m
a
c
e
ut
i
c
a
l
B
i
o
l
o
g
y
,
F
a
c
u
l
t
y
o
f
P
h
a
r
m
a
c
y
,
Ahm
a
d
Da
hl
a
n
U
ni
ve
r
s
i
t
y
,
Yo
g
y
a
ka
r
t
a
,
I
n
do
n
e
s
i
a
.
T
e
s
t
r
e
s
u
l
t
s
o
f
bi
o
a
c
t
i
ve
c
o
n
t
e
n
t
f
r
o
m
B
C
S
O
s
h
o
we
d
f
a
t
t
y
a
c
i
ds
(
78%
)
a
n
d
s
m
a
ll
a
m
o
u
n
t
s
o
f
t
hym
o
qu
i
n
o
n
e
.
As
a
n
i
mm
u
n
o
s
uppr
e
s
s
i
ve
i
nduc
i
ng
a
ge
n
t
us
e
d
7,
12
-
d
i
m
e
t
hy
l
be
nz
[
a
]
a
n
t
h
r
a
c
e
n
e
(
DM
B
A
)
(
>
9
5%
)
w
i
t
h
s
y
n
o
nym
1,
4
-
D
i
m
e
t
hyl
-
2,
3
-
b
e
n
z
o
phe
n
a
n
t
h
r
i
d
i
ne
,
9,
10
-
Di
m
e
t
hyl
-
1,
2
-
b
e
n
z
a
n
t
h
r
a
c
e
ne
(
C
20H16)
o
b
t
a
i
n
e
d
f
r
o
m
S
i
g
m
a
-
Al
dr
i
c
h
(
c
a
t
.
D3254)
.
A
s
a
po
s
i
t
i
v
e
c
o
n
t
r
o
l
,
t
w
o
i
n
gr
e
d
i
e
n
t
s
we
r
e
us
e
d,
n
a
m
e
ly
,
t
hym
o
qu
i
n
o
n
e
a
n
d
t
a
m
o
xi
f
e
n
.
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hym
o
qu
i
n
o
ne
us
e
d
a
s
a
po
s
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t
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ve
c
o
n
t
r
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l
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s
2
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s
o
pr
o
py
l
-
5
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m
e
t
hyl
-
1,
4
-
b
e
n
z
o
qu
i
n
o
n
e
(
>
98%
)
O
b
t
a
i
n
e
d
f
r
o
m
S
i
g
m
a
-
A
l
dr
i
c
h
(
c
a
t
.
27466
6)
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ge
n
t
,
whi
l
e
t
a
m
o
xif
e
n
(
T
a
m
o
xif
e
n
,
K
a
l
be
F
a
r
m
a
)
wa
s
pur
c
h
a
s
e
d
f
r
o
m
a
p
h
a
r
m
a
c
y
.
S
a
r
d
ji
t
o
'
s
Ho
s
p
i
t
a
l
w
i
t
h
pr
e
s
c
r
i
bi
ng
f
r
o
m
t
h
e
do
c
to
r
.
C
or
n
o
i
l
a
s
DM
B
A
(
l
i
po
phil
i
c
)
s
o
l
v
e
n
t
wa
s
o
b
t
a
i
n
e
d
f
r
o
m
S
i
g
m
a
-
Al
dr
i
c
h
(
c
a
t
.
C
8267)
.
Al
l
m
a
t
e
r
i
a
l
s
o
r
i
g
i
na
t
i
n
g
f
r
o
m
S
i
g
m
a
-
Al
dr
i
c
h
we
r
e
o
b
t
a
i
n
e
d
t
h
r
o
ugh
o
f
f
i
c
i
a
l
a
ge
nt
s
i
n
Yo
gy
a
ka
r
t
a
.
M
a
t
e
r
i
a
l
s
f
o
r
t
h
e
t
e
s
t
o
f
C
D4T
h
e
l
p
e
r
a
n
d
C
D4
C
D25T
r
e
g
c
e
l
l
c
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i
o
s
c
i
e
n
c
e
s
F
A
C
S
a
n
d
C
e
ll
Que
s
t
we
r
e
us
e
d
to
de
t
e
r
m
i
ne
C
D4
a
n
d
C
D4C
D25
c
o
un
t
s
.
2.
4.
Dat
a
an
al
ys
is
T
h
e
m
e
a
n
d
i
f
f
e
r
e
n
c
e
o
f
t
h
e
n
u
m
be
r
o
f
l
e
uko
c
y
t
e
c
e
ll
s
,
t
h
e
n
u
m
be
r
o
f
C
D4,
a
n
d
C
D4
C
D25
lym
p
h
o
c
y
t
e
s
b
e
t
we
e
n
t
h
e
gr
o
ups
we
r
e
d
o
n
e
by
AN
OV
A
t
e
s
t
a
n
d
f
o
l
l
o
we
d
by
m
u
l
t
i
p
l
e
c
o
m
pa
r
i
s
o
n
t
e
s
t
s
w
i
t
h
a
95%
c
o
nf
i
de
n
c
e
l
e
v
e
l
.
3.
RE
S
UL
T
S
A
ND
DI
S
CU
S
S
I
ON
3.
1.
Num
b
e
r
an
d
t
yp
e
of
l
e
u
k
oc
yt
e
s
T
h
e
m
e
a
s
ur
e
m
e
n
t
r
e
s
u
l
t
s
o
f
t
h
e
n
u
m
be
r
o
f
l
e
uko
c
y
t
e
t
y
pe
s
a
r
e
pr
e
s
e
n
t
e
d
i
n
T
a
bl
e
1.
L
e
uko
c
y
t
e
s
a
r
e
t
h
e
f
i
r
s
t
n
a
t
ur
a
l
de
f
e
n
c
e
s
r
e
s
po
ns
i
bl
e
f
o
r
e
l
im
i
n
a
t
i
n
g
pa
t
h
o
ge
ns
t
h
a
t
e
n
t
e
r
t
h
e
bl
o
o
ds
t
r
e
a
m
.
T
h
e
n
o
r
m
a
l
l
e
uko
c
y
t
e
c
o
un
t
i
n
S
pr
a
gue
Da
w
l
e
y
r
a
t
s
,
a
c
c
o
r
di
ng
to
S
c
h
a
l
m
's
ve
t
e
r
i
n
a
r
y
h
a
e
m
a
t
o
l
o
g
y
[
19
]
i
s
9.
810±
1.
789
106
c
e
l
l
s
/
mm
3)
.
T
h
e
n
u
m
be
r
o
f
l
e
uko
c
y
t
e
s
i
n
t
h
e
h
e
a
l
t
hy
gr
o
up
a
t
we
e
k
27
wa
s
6.
33±
1.
37
(
106
c
e
l
ls
/
m
m
3)
,
whi
c
h
wa
s
l
o
we
r
t
h
a
n
t
h
e
n
u
m
be
r
o
f
l
e
uko
c
y
t
e
s
by
S
c
h
a
l
m
.
T
a
bl
e
1
s
h
o
ws
t
h
a
t
DM
B
A
i
nduc
t
i
o
n
de
c
r
e
a
s
e
s
th
e
n
u
m
be
r
o
f
l
e
uko
c
y
t
e
s
.
T
h
e
l
e
uko
c
y
t
e
s
i
n
t
h
e
n
o
r
m
a
l
gr
o
up
(
6.
33±
1.
37
(
106
c
e
l
l
s
/
mm
3)
)
we
r
e
di
f
f
e
r
e
n
t
f
r
o
m
t
h
o
s
e
i
n
t
h
e
DM
B
A
gr
o
up
(
2.
80±
1.
10
(
106
c
e
l
l
s
/
mm
3)
)
(
p
<
0.
05)
.
T
h
e
D
M
B
A
gr
o
up
ha
d
t
h
e
l
o
w
e
s
t
a
ve
r
a
ge
l
e
uko
c
y
t
e
c
o
un
t
.
T
h
e
B
C
S
O
gr
o
up
h
a
d
hi
g
h
e
r
a
ve
r
a
ge
l
e
uko
c
y
t
e
c
o
un
t
t
h
a
n
t
h
a
t
i
n
t
h
e
D
M
B
A
gr
o
up
(
p
<
0.
05)
.
T
h
e
B
C
S
O
gr
o
ups
h
a
d
r
e
l
a
t
i
v
e
ly
t
h
e
s
a
m
e
n
u
m
be
r
o
f
l
e
uko
c
y
t
e
s
a
s
t
h
e
n
o
r
m
a
l
,
t
hym
o
qu
i
n
o
ne
,
a
n
d
t
a
m
o
xif
e
n
gr
o
ups
.
T
h
e
B
C
S
O6.
8
gr
o
up
h
a
d
t
h
e
hi
g
h
e
s
t
l
e
uko
c
y
t
e
c
oun
t
,
hi
g
h
e
r
t
h
a
n
t
h
e
n
o
r
m
a
l
,
t
hy
m
o
qu
i
n
o
n
e
a
n
d
t
a
m
o
xi
f
e
n
gr
o
ups
(
p
<
0.
05)
.
DM
B
A
i
nduc
t
i
o
n
r
e
duc
e
s
t
h
e
n
u
m
be
r
o
f
lym
p
h
o
c
y
t
e
s
a
n
d
i
nc
r
e
a
s
e
s
t
h
e
n
u
m
be
r
o
f
n
e
ut
r
o
phi
l
s
a
n
d
m
o
n
o
c
y
t
e
s
.
T
h
e
n
u
m
be
r
o
f
l
ym
p
h
o
c
y
t
e
s
a
n
d
m
o
no
c
y
t
e
s
i
n
t
h
e
D
M
B
A
gr
o
u
p
wa
s
l
o
we
r
t
h
a
n
t
h
a
t
o
f
i
n
t
h
e
h
e
a
l
t
hy
a
n
d
s
o
l
v
e
n
t
gr
o
ups
(
p
<
0.
05)
.
Ho
we
v
e
r
,
th
e
n
u
m
be
r
o
f
n
e
ut
r
o
phi
l
s
i
n
t
h
e
DM
B
A
gr
o
up
wa
s
hi
g
h
e
r
t
h
a
n
t
h
a
t
o
f
t
h
e
h
e
a
l
t
hy
gr
o
up
(
50
.
80±
5.
54
c
o
m
p
a
r
e
d
to
30.
67±
4.
23
)
(
p<
0
.
05)
.
B
C
S
O,
t
hy
m
o
qu
i
no
n
e
,
a
n
d
t
a
m
o
xif
e
n
pr
e
ve
n
t
a
de
c
r
e
a
s
e
i
n
t
h
e
n
u
m
be
r
o
f
l
ym
p
h
o
c
y
t
e
s
a
n
d
m
o
n
o
c
y
t
e
s
due
t
o
DM
B
A
i
n
duc
t
i
o
n
.
T
h
e
n
u
m
be
r
o
f
lym
p
h
o
c
y
t
e
s
a
n
d
m
o
n
o
c
y
t
e
s
i
n
t
h
e
B
C
S
O,
t
hy
m
o
qu
i
n
o
n
e
a
n
d
t
a
m
o
xi
f
e
n
gr
o
ups
wa
s
hi
g
h
e
r
t
h
a
n
t
h
a
t
o
f
i
n
t
h
e
DM
B
A
gr
o
up
(
p<
0
.
05)
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t
.
J
.
P
ubl
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c
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a
l
t
h
S
c
i
.
I
S
S
N:
2252
-
8806
B
lack
c
umin
s
e
e
d
oil
incr
e
as
e
leuc
oc
y
te
and
C
D4Thelpe
r
numbe
r
in
s
pr
ague
-
da
w
ley
r
at
s
…
(
T
it
iek
Hi
day
ati
)
241
T
a
bl
e
1.
T
h
e
m
e
a
s
ur
e
m
e
n
t
r
e
s
u
l
t
s
o
f
t
h
e
n
u
m
b
e
r
a
n
d
c
o
un
t
o
f
l
e
uko
c
y
t
e
t
y
pe
s
i
n
t
h
e
DM
B
A
-
i
nduc
e
d
S
D
r
a
t
s
a
t
a
d
o
s
e
o
f
2x
20
m
g
/
kg
B
W
/
we
e
k
f
o
r
5
w
e
e
ks
a
f
t
e
r
r
e
c
e
i
vi
n
g
B
C
S
O
(
a
t
d
o
s
e
s
o
f
6.
8,
68
a
n
d
136
mg
/
kg
B
W
)
,
t
hy
m
o
qu
i
n
o
n
e
(
50
m
g
/
kg
B
W
/
da
y
)
a
n
d
t
a
m
o
xif
e
n
(
60
m
g
/
kg
B
W
/
da
y
)
f
o
r
14
da
y
s
b
e
f
o
r
e
a
n
d
dur
i
n
g
i
n
duc
t
i
o
n
.
B
l
o
o
d
c
o
l
l
e
c
t
i
o
n
wa
s
do
n
e
a
t
we
e
k
27.
T
h
e
s
o
l
v
e
n
t
gr
o
up
r
e
c
e
i
v
e
d
c
o
r
n
o
i
l
a
t
a
d
o
s
e
o
f
100
mg
/
kg
B
W
/
da
y
w
i
t
h
o
ut
DM
B
A
i
n
duc
t
i
o
n
G
r
o
ups
n
numbe
r
of
le
uk
oc
y
te
s
(
x
10
6
)
(
me
a
n±S
D
)
pe
r
c
e
nt
a
ge
of
ne
ut
r
o
phi
ls
(
me
a
n±S
D
)
pe
r
c
e
nt
a
ge
of
l
y
mph
oc
y
t
e
s
(
me
a
n±S
D
)
pe
r
c
e
nt
a
ge
of
mo
n
oc
y
t
e
s
(
me
a
n±S
D
)
pe
r
c
e
nt
a
ge
of
e
o
s
in
o
ph
il
s
(
me
a
n±S
D
)
N
o
r
ma
l
12
6.33±1.37
30.67±4.23
61.67±3.61
6.33±0.52
1.33±0.52
B
C
S
O
6.8
12
9.86±0.90
b
33.57±0.98
b
53.71±1.80
b
10.86±1.07
b
1.86±1.07
B
C
S
O
68
12
6.29±0.49
b
27.14±3.63
b
65.14±3.58
b
6.14±0.89
b
1.57±0.53
B
C
S
O
136
12
7.00±0.93
b
27.75±1.67
b
65.13±0.83
b
5.75±1.04
b
1.38±0.52
T
h
y
m
oqui
n
o
ne
12
6.86±0.90
b
28.14±1.68
b
64.71±1.11
b
5.71±0.95
b
1.43±0.53
T
a
m
ox
i
f
e
n
12
7.00±2.68
b
35.53±8.64
b
57.50±7.12
b
5.67±1.86
b
1.33±0.52
D
M
B
A
12
2.80±1.10
*
50.80±5.54
*
44.40±2.51
*
3.20±1.64
*
1.60±1.52
S
o
l
ve
nt
12
6.67±1.03
b
30.67±4.23
b
61.67±3.72
b
6.33±0.52
b
1.33±0.52
no
t
e
:
*
=
p<
0.05 to
n
or
ma
l
gr
o
up;
b=
p<
0.05 to
D
M
B
A
g
r
o
up
3.
2.
Num
b
e
r
of
CD
4
T
h
an
d
CD
4CD
25
T
r
e
g
T
h
e
C
D4
T
hi
s
a
l
ym
p
h
o
c
y
t
e
t
h
a
t
pl
a
y
s
a
r
o
l
e
i
n
r
e
gu
l
a
t
i
n
g
s
pe
c
if
i
c
c
e
ll
u
l
a
r
i
mm
u
n
e
r
e
s
po
n
s
e
s
w
hi
le
C
D4C
D25T
r
e
g
a
c
t
s
a
s
a
r
e
gul
a
t
o
r
o
f
t
o
l
e
r
a
n
c
e
r
e
s
po
n
s
e
a
n
d
pr
e
v
e
n
t
s
hy
pe
r
s
e
n
s
i
t
i
v
i
t
y
r
e
a
c
t
i
o
ns
.
C
D4
T
h
a
n
d
C
D4C
D25
T
r
e
g
t
e
s
t
r
e
s
ul
t
s
w
i
t
h
f
l
o
w
c
y
t
o
m
e
t
e
r
a
r
e
p
r
e
s
e
n
t
e
d
i
n
T
a
bl
e
2.
T
a
bl
e
2
.
T
h
e
m
e
a
s
ur
e
m
e
n
t
r
e
s
u
l
t
s
o
f
t
h
e
a
b
s
o
l
ut
e
nu
m
b
e
r
o
f
C
D4
T
He
l
pe
r
&
C
D4C
D5
T
r
e
gu
l
a
t
or
a
n
d
pe
r
c
e
n
t
a
ge
o
f
C
D4C
D25T
r
e
g
i
n
t
h
e
DM
B
A
-
i
n
du
c
e
d
S
D
r
a
t
s
a
t
a
d
o
s
e
o
f
2x
20
m
g
/
kg
B
W
/
we
e
k
f
o
r
5
we
e
ks
a
f
t
e
r
r
e
c
e
i
vi
ng
B
C
S
O
(
a
t
d
o
s
e
s
o
f
6.
8,
68
a
n
d
13
6
mg
/
kg
B
W
)
,
t
hy
m
o
qu
i
n
o
n
e
(
50
m
g
/
kg
B
W
/
da
y
)
a
n
d
t
a
m
o
xif
e
n
(
60
m
g
/
kg
B
W
/
da
y
)
f
o
r
14
da
y
s
be
f
o
r
e
a
n
d
dur
i
n
g
i
n
du
c
t
i
o
n
.
B
l
o
o
d
c
o
l
l
e
c
t
i
o
n
wa
s
do
n
e
a
t
we
e
k
27.
T
h
e
s
o
l
v
e
n
t
gr
o
up
r
e
c
e
i
ve
d
c
o
r
n
o
i
l
a
t
a
do
s
e
o
f
100
mg
/
kg
B
W
/
da
y
w
i
t
h
o
ut
DM
B
A
i
n
duc
t
i
o
n
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N:
2252
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8806
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t
h
e
B
C
S
O
gr
o
up
o
f
68
a
n
d
136
m
g/kg
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/da
y
a
n
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m
a
y
b
e
s
a
f
e
r
w
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m
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ll
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r
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s
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.
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h
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l
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t
i
v
e
a
n
d
i
mm
u
n
o
m
o
du
l
a
t
o
r
y
[
16
-
17,
20
-
22
]
.
Da
t
a
f
r
o
m
t
hi
s
s
t
ud
y
s
uppo
r
t
t
h
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l
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o
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vio
us
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t
udi
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a
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ly
t
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f
f
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t
o
f
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O
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t
h
e
nu
m
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o
f
C
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D25T
r
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g.
C
D4C
D25T
r
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g
l
ym
p
h
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ve
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f
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C
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O
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a
ut
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a
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e
.
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h
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t
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f
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t
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m
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pe
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f
f
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c
t
o
f
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C
S
O
o
n
a
uto
i
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n
e
d
i
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e
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e
.
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h
e
r
e
s
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l
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f
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o
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l
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im
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ve
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pe
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O
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m
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ur
v
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il
l
a
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m
p
li
f
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e
r
[
8,
15,
20]
.
F
i
r
s
t
de
v
e
l
o
pe
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by
P
a
u
l
E
h
r
li
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e
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c
e
n
t
ur
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t
h
e
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o
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o
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i
mm
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ur
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l
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a
s
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m
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h
a
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n
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y
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m
h
a
s
a
r
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l
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n
pr
e
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n
g
a
n
d
li
mi
t
i
ng
t
u
m
o
ur
gr
o
w
t
h
[
7,
8,
23]
i
nc
l
ud
i
ng
t
h
e
pr
o
c
e
s
s
o
f
c
a
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c
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.
R
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s
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a
r
c
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y
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l
a
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to
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n
d
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D4
T
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ly
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s
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p
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by
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h
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I
L
-
2,
I
L
-
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a
n
d
I
F
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D8
c
y
t
o
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l
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p
h
o
c
y
t
e
s
[
8]
.
I
t
h
a
s
b
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m
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t
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a
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t
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f
I
L
-
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c
y
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by
m
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t
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t
h
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t
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o
f
pr
o
s
t
a
gl
a
n
d
i
n
pr
o
duc
t
i
o
n
[
15,
21
-
22,
24
]
.
A
r
e
a
s
o
na
bl
e
a
m
o
u
n
t
o
f
C
D4
C
D25
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r
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g
s
e
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to
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e
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a
t
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h
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e
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s
po
n
s
e
,
b
ut
e
x
c
e
s
s
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ve
C
D4C
D25T
r
e
g
c
o
un
t
i
s
im
m
u
n
o
s
uppr
e
s
s
i
ve
[
25
-
26]
.
Da
t
a
f
r
o
m
t
hi
s
s
t
ud
y
i
n
d
i
c
a
t
e
t
h
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t
DM
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A
in
duc
t
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n
de
c
r
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a
s
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t
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ot
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l
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n
t
o
f
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t
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n
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t
o
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ll
s
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.
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r
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t
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t
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s
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x
c
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s
s
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ve
[
9,
25
-
2
6]
,
b
u
t
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f
t
h
e
C
D4C
D25
T
r
e
g
c
o
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t
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t
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m
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.
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t
o
C
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h
i
s
l
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we
r
o
r
e
qua
l
to
10
%
[
27]
.
I
n
t
h
e
s
e
i
de
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l
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d
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t
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o
ns
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T
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n
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m
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ne
r
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r
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mm
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n
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de
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i
c
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n
c
y
.
B
a
s
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o
n
t
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h
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r
c
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n
t
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ge
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f
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D4
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r
e
g
to
C
D4T
h
i
s
l
o
we
r
o
r
e
qua
l
t
o
10%
[
27]
.
I
n
t
h
e
s
e
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de
a
l
c
o
n
d
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t
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o
n
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T
r
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a
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y
.
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t
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t
DM
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A
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t
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s
C
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r
e
g
c
o
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t.
T
h
e
l
o
w
C
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t
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to
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h
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s
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due
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A
m
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m
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s
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s
s
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n
d
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m
a
t
oto
xi
c
[
15,
24]
.
B
C
S
O
a
d
m
i
n
i
s
t
r
a
t
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o
n
i
nc
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d
t
he
a
bs
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l
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a
m
o
un
t
o
f
C
D4C
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T
r
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g
b
ut
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e
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s
e
d
t
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pe
r
c
e
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t
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ge
o
f
C
D4C
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r
e
g
to
C
D4.
T
h
e
B
C
S
O,
t
hy
m
o
qu
i
n
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n
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xif
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n
gr
o
ups
h
a
d
hi
g
h
e
r
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T
r
e
g
a
b
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e
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m
be
r
s
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a
n
t
h
e
D
M
B
A
gr
o
up
b
ut
ha
d
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r
C
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pe
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4.
CONC
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Evaluation Warning : The document was created with Spire.PDF for Python.
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Evaluation Warning : The document was created with Spire.PDF for Python.