AA

SL

D, T

he

Liv

er M

eeti

ng

in B

ost

on

, MA

, Oct

ob

er 2

9 –N

ove

mb

er 2

, 201

0

RE

SU

LT

S (c

ont’d

)

Co

adm

inis

trat

ion

of

BM

S-7

9005

2 an

d B

MS

-650

032

Do

es N

ot

Res

ult

in a

Clin

ical

ly

Mea

nin

gfu

l Ph

arm

aco

kin

etic

Inte

ract

ion

in H

ealt

hy

Su

bje

cts

Med

Pos

10_0

139C

Bif

ano

M1 ,

Sev

insk

yH

,1B

edfo

rd B

,1C

ou

mb

isJ,

1E

ley

T,1

Hu

ang

SP

,1M

edlo

ck M

,2G

rase

laD

M,1

Ber

tzR

1

1 Bris

tol-M

yers

Squ

ibb,

Res

earc

h an

d D

evel

opm

ent,

Hop

ewel

l, N

J, U

nite

d S

tate

s; 2 P

PD

Dev

elop

men

t, LP

, Aus

tin, T

X, U

nite

d S

tate

s.

AB

ST

RA

CT

Bac

kgro

un

d:

NS

5A p

lays

a c

entr

al r

ole

in v

iral r

eplic

atio

n of

hep

atiti

s C

viru

s (H

CV

).

BM

S-7

9005

2 is

a fi

rst-

in-c

lass

and

pot

ent N

S5A

Inhi

bito

r w

ith b

road

gen

otyp

ic c

over

age.

B

MS

-650

032

is a

pot

ent H

CV

NS

3 in

hibi

tor

with

in v

itro

activ

ity a

gain

st g

enot

ypes

1a

and

1b. P

roof

-of-

conc

ept m

ultip

le-d

ose

stud

ies

in H

CV

sub

ject

s fo

r ea

ch c

ompo

und

dem

onst

rate

d a

robu

st d

eclin

e in

HC

V R

NA

whe

n ad

min

iste

red

as m

onot

hera

py.

Com

bina

tions

of 2

or

mor

e di

rect

-act

ing

antiv

iral (

DA

A)

agen

ts a

re e

xpec

ted

to b

e pa

rt o

f fu

ture

HC

V th

erap

y; th

eref

ore,

ass

essm

ent o

f a p

oten

tial d

rug-

drug

inte

ract

ion

with

thes

e 2

com

poun

ds to

geth

er is

war

rant

ed p

rior

to c

omm

ence

men

t of c

linic

al tr

ials

in H

CV

pat

ient

s.

Met

ho

ds:

The

obj

ectiv

e of

this

ope

n-la

bel,

rand

omiz

ed, m

ultip

le-d

ose

stud

y w

as to

ass

ess

the

phar

mac

okin

etic

s (P

K),

saf

ety,

and

tole

rabi

lity

of B

MS

-790

052

and

BM

S-6

5003

2 w

hen

coad

min

iste

red

in h

ealth

y su

bjec

ts fo

r 14

day

s. S

ubje

cts

rece

ived

eith

er 6

0 m

gB

MS

-79

0052

QD

or

600

mg

BM

S-6

5003

2 Q

12h

for

7 da

ys d

urin

g a

lead

-in p

erio

d, fo

llow

ed b

y co

adm

inis

trat

ion

of 3

0 m

g B

MS

-790

052

QD

and

200

mg

BM

S-6

5003

2 Q

12h

for

14 d

ays.

P

lasm

a co

ncen

trat

ions

wer

e ob

tain

ed v

ia li

quid

chr

omat

ogra

phy-

tand

em m

ass

spec

tros

copy

. Geo

met

ric m

ean

ratio

s (G

MR

) an

d 90

% c

onfid

ence

inte

rval

s (C

I) fo

r B

MS

-79

0052

and

BM

S-6

5003

2 P

K w

ere

estim

ated

by

gene

ral l

inea

r m

ixed

effe

cts

mod

els.

Res

ult

s:B

MS

-790

052

and

BM

S-6

5003

2 ex

posu

res

follo

win

g re

spec

tive

dose

s of

30

mg

QD

and

200

mg

Q12

h ad

min

iste

red

toge

ther

wer

e co

mpa

rabl

e to

his

toric

al d

ata

for

sim

ilar

dose

s of

eac

h co

mpo

und

adm

inis

tere

d al

one.

The

GM

R (

90%

CI)

for

BM

S-7

9005

2 an

d B

MS

-650

032

AU

C[T

AU

]w

ere

1.15

6 (0

.895

,1.4

91)

and

1.02

5 (0

.734

,1.4

33),

res

pect

ivel

y.

Fol

low

ing

dose

nor

mal

izat

ion

to 6

0 m

g, B

MS

-790

052

expo

sure

(A

UC

[TA

U])

afte

r co

adm

inis

trat

ion

of 3

0 m

g Q

D w

ith B

MS

-650

032

200

mg

Q12

h fo

r 14

day

s w

as s

imila

r to

ex

posu

re o

bser

ved

follo

win

g 7

days

of B

MS

-790

052

60 m

g Q

D in

the

lead

-in p

erio

d, w

ith a

G

MR

(90

% C

I) o

f 1.2

02 (

1.11

3,1.

298 )

. Fol

low

ing

dose

nor

mal

izat

ion

to 6

00 m

g Q

12h,

B

MS

-650

032

expo

sure

(A

UC

[TA

U])

afte

r co

adm

inis

trat

ion

of 2

00 m

g Q

12h

with

BM

S-7

9005

2 30

mg

QD

was

sim

ilar

to e

xpos

ure

obse

rved

in th

e le

ad-in

per

iod,

with

a G

MR

(90

% C

I) o

f 0.

868

(0.7

26,1

.038

).

Co

ncl

usi

on

s:C

oadm

inis

trat

ion

of B

MS

-790

052

and

BM

S-6

5003

2 in

hea

lthy

subj

ects

did

no

t res

ult i

n a

clin

ical

ly m

eani

ngfu

l PK

inte

ract

ion;

a c

linic

ally

mea

ning

ful P

K in

tera

ctio

n is

no

t ant

icip

ated

whe

n B

MS

-790

052

and

BM

S-6

5003

2 ar

e co

adm

inis

tere

din

HC

V p

atie

nts.

B

ased

on

the

resu

lts o

f thi

s st

udy,

a c

linic

al tr

ial w

ith B

MS

-790

052

and

BM

S-6

5003

2, b

oth

with

and

with

out p

egyl

ated

inte

rfer

on/r

ibav

irin,

has

com

men

ced

to a

sses

s th

e ef

fect

of d

ual

NS

5A p

lus

NS

3 in

hibi

tion

in H

CV

ther

apy.

Coa

dmin

istr

atio

nof

BM

S-7

9005

2 30

mg

QD

and

BM

S-6

5003

2 20

0 m

g Q

12h

for

14 d

ays

did

not r

esul

t in

a cl

inic

ally

mea

ning

ful P

K in

tera

ctio

nC

oadm

inis

trat

ion

of B

MS

-790

052

30 m

g Q

D a

nd B

MS

-650

032

200

mg

Q12

h fo

r 14

day

s w

as w

ell-t

oler

ated

in th

is s

tudy

A d

ose-

depe

nden

t AM

/PM

diff

eren

ce w

as o

bser

ved

for

BM

S-6

5003

2 ex

posu

re,w

hich

m

ay b

e du

e to

the

tem

pora

l rel

atio

nshi

p of

food

and

BM

S-6

5003

2 ad

min

istr

atio

n

Stu

dies

of p

oten

tial d

rug-

drug

inte

ract

ion

betw

een

DA

A a

gent

s ar

e in

crea

sing

ly

impo

rtan

t, as

futu

re H

CV

ther

apy

is e

xpec

ted

to in

clud

e D

AA

com

bina

tion

ther

apy

BM

S-7

9005

2, a

first

-in-c

lass

,pot

entH

CV

NS

5A in

hibi

tor,

and

BM

S-6

5003

2, a

high

lyac

tive

HC

V N

S3

inhi

bito

r, h

ave

both

sho

wn

sign

ifica

nt a

ntiv

iral a

ctiv

ity a

s m

onot

hera

py

or w

hen

com

bine

d w

ith p

egyl

ated

inte

rfer

on/r

ibav

irin

in s

ubje

cts

with

chr

onic

HC

V

infe

ctio

n an

d ar

e ex

celle

nt c

andi

date

s fo

r us

e to

geth

er in

com

bina

tion

ther

apy

The

prim

ary

obje

ctiv

e of

this

stu

dy w

as to

ass

ess

the

PK

of B

MS

-790

052

and

BM

S-6

5003

2 w

hen

coad

min

iste

red,

rel

ativ

e to

adm

inis

trat

ion

of e

ach

alon

eT

he s

econ

dary

obj

ectiv

e w

as to

ass

ess

the

safe

ty a

nd to

lera

bilit

y of

BM

S-7

9005

2 an

d B

MS

-650

032

whe

n co

adm

inis

tere

dan

d ad

min

iste

red

alon

e

No

ncl

inic

al B

ackg

rou

nd

an

d S

tud

y D

esig

n R

atio

nal

eO

ne-m

onth

ora

l tox

icity

com

bina

tion

stud

ies

with

BM

S-7

9005

2 an

d B

MS

-650

032

in r

ats

and

mon

keys

did

not

iden

tify

any

clin

ical

find

ings

or

uniq

ue to

xici

ty; t

he to

xico

logi

cpr

ofile

was

sim

ilar

to th

e fin

ding

s ob

serv

ed in

the

sing

le to

xici

ty s

tudi

es w

ith n

o ov

erla

ppin

g to

xici

tyT

oxic

okin

etic

eval

uatio

n in

mon

keys

dem

onst

rate

d a

~2-

fold

incr

ease

in th

e ex

posu

re o

f B

MS

-790

052

whe

n co

adm

inis

tere

dw

ith B

MS

-650

032

Tox

icok

inet

icev

alua

tion

in m

onke

ys d

emon

stra

ted

a ~

2-to

15-

fold

incr

ease

in th

e ex

posu

re o

f BM

S-6

5003

2 w

hen

coad

min

iste

red

with

BM

S-7

9005

2B

ased

on

thes

e an

imal

find

ings

, whi

ch s

ugge

st a

pot

entia

l dru

g-dr

ug in

tera

ctio

n in

viv

o,

the

curr

ent s

tudy

was

des

igne

d w

ith a

lead

-in p

hase

at h

ighe

r do

ses

and

a co

mbi

natio

n ph

ase

at lo

wer

dos

es

Stu

dy

Des

ign

BA

CK

GR

OU

ND

AN

D O

BJE

CT

IVE

S

DIS

CL

OS

UR

ES

Bifa

noM

, Sev

insk

yH

, Bed

ford

B, C

oum

bis

J, E

ley

T, H

uang

SP

, Gra

sela

DM

, and

Ber

tzR

are

em

ploy

ees

of B

risto

l-Mye

rs S

quib

b M

edlo

ck M

: No

disc

losu

res

to r

epor

t

RE

SU

LT

S (c

ont’d

)A

tota

l of 2

8 he

alth

y m

ale

and

fem

ale

subj

ects

wer

e ra

ndom

ly a

ssig

ned

to in

itial

tr

eatm

ent w

ith B

MS

-790

052

(n=

14)

or B

MS

-650

032

(n=1

4)M

orni

ng d

oses

of B

MS

-790

052

and

BM

S-6

5003

2 w

ere

adm

inis

tere

d fo

llow

ing

an

over

nigh

t fas

t; ev

enin

g do

ses

of B

MS

-650

032

wer

e ad

min

iste

red

afte

r at

leas

t a

2-ho

ur fa

stP

K p

aram

eter

s fo

r B

MS

-650

032

and

BM

S-7

9005

2 w

ere

deriv

ed fr

om p

lasm

a co

ncen

trat

ion

vstim

e da

ta b

y no

ncom

part

men

tala

naly

sis

usin

g th

e pr

ogra

m K

inet

ica

Saf

ety

asse

ssm

ents

wer

e ba

sed

on r

epor

ted

adve

rse

even

ts a

nd th

ere

sults

of v

ital s

ign

mea

sure

men

ts, p

hysi

cal e

xam

inat

ions

, EC

Gs,

and

clin

ical

labo

rato

ry te

sts

Tre

atm

ent

AB

MS

-650

032

600

mg

Q12

h x

7 da

ys

Tre

atm

ent

BB

MS

-790

052

60 m

g Q

Dx

7 da

ys

Tre

atm

ent

CB

MS

-650

032

200

mg

Q12

h +

BM

S-7

9005

2 30

mg

QD

x 14

day

s

Scr

eeni

ng,

Enr

ollm

ent,

Ran

dom

izat

ion

Stu

dyD

isch

arge

Day

128

112-

427 PK

PK

ME

TH

OD

S

BM

S-7

9005

2 P

lasm

a P

rofi

les

0

200

400

600

800

1000

1200

1400

1600

1800

2000

04

812

1620

24

Tim

e (h

)

Mean + SD [BMS-790052] (ng/mL)

BM

S-7

9005

2 60

mg

QD

(da

y 7,

n=1

4)

BM

S-7

9005

2 30

mg

QD

+ B

MS

-650

032

200

mg

Q12

h (d

ay 2

1, n

=26)

BM

S-7

9005

2 S

tati

stic

al A

nal

ysis

Do

se-n

orm

aliz

ed s

tati

stic

al a

nal

ysis

: B

MS

-790

052

30 m

g Q

D c

oad

min

iste

red

wit

h

BM

S-6

5003

2 20

0 m

g Q

12h

(T

RT

C)

rela

tive

to

BM

S-7

9005

2 60

mg

QD

(T

RT

B)

AU

C =

are

a un

der

the

conc

entr

atio

n vs

time

curv

e; C

max

= m

axim

um o

bser

ved

conc

entr

atio

n; C

min

= m

inim

um o

bser

ved

conc

entr

atio

n.

PK

P

aram

eter

TR

T B

BM

S-7

9005

2 60

mg

Q

DG

eo M

ean

(C

V)

TR

T C

BM

S-7

9005

2 30

mg

QD

+

BM

S-6

5003

2 20

0 m

g Q

12h

Geo

Mea

n (

CV

)N

orm

aliz

ed t

o 6

0-m

g D

ose

GM

R (

90%

CI)

AU

C(T

AU

)12

074

(25)

1451

5 (2

8)1.

202

(1.1

13, 1

.298

)

Cm

ax14

96 (

24)

1599

(26

)1.

069

(0.9

71, 1

.176

)

Cm

in16

3 (3

9)21

7 (3

5)1.

330

(1.2

21, 1

.449

)

Whe

n B

MS

-790

052

30 m

g Q

D w

as n

orm

aliz

ed to

a d

ose

of 6

0 m

g Q

D, B

MS

-790

052

AU

C(T

AU

), C

max

, and

Cm

inw

ere

sim

ilar

to th

ose

obse

rved

with

60

mg

QD

alo

ne

BM

S-7

9005

2 C

urr

ent

Stu

dy

(Stu

dy

AI4

4700

9) v

sH

isto

rica

l Dat

a (S

tud

y A

I444

003)

Sta

tist

ical

an

alys

is:

BM

S-7

9005

2 30

mg

QD

co

adm

inis

tere

dw

ith

BM

S-6

5003

2 20

0 m

g Q

12h

(T

RT

C)

rela

tive

to

BM

S-7

9005

2 30

mg

QD

his

tori

cal d

ata

Exp

osur

es o

f BM

S-7

9005

2 30

mg

QD

whe

n co

adm

inis

tere

dw

ith B

MS

-650

032

wer

e co

mpa

rabl

e to

his

toric

al d

ata

for

BM

S-7

9005

2 30

mg

QD

adm

inis

tere

d al

one

PK

Par

amet

erS

tud

y A

I447

009

(BM

S-7

9005

2 +

BM

S-6

5003

2)

Stu

dy

AI4

4400

3 (B

MS

-790

052

Alo

ne)

GM

R (

90%

CI)

AU

C(T

AU

)72

51 (

28)

6275

(39

)1.

156

(0.8

95, 1

.491

)

Cm

ax79

9 (2

6)73

4 (3

0)1.

089

(0.8

64, 1

.374

)

Cm

in10

8 (3

5)92

(54

)1.

172

(0.8

48, 1

.620

)

BM

S-6

5003

2 P

lasm

a P

rofi

les

050100

150

200

250

300

350

400

02

46

810

12

Tim

e (h

)

Mean [BMS-650032] (ng/mL)

200

mg

Q12

h D

ay 2

1

PM

AM

0

500

1000

1500

2000

2500

3000

3500

4000

4500

04

812

1620

24

Tim

e (h

)

Mean + SD [BMS-650032] (ng/mL)

Day

7 (

BM

S-6

5003

2 60

0 m

g Q

12h,

n=

14)

Day

21

(BM

S-6

5003

2 20

0 m

g Q

12h

+ B

MS

-790

052

30 m

g Q

D, n

=26

)

BM

S-6

5003

2 S

tati

stic

al A

nal

ysis

Do

se-N

orm

aliz

ed

PK

Par

amet

er

TR

T A

BM

S-6

5003

2 60

0 m

g

Q12

hG

eo M

ean

(C

V)

TR

T C

BM

S-7

9005

2 30

mg

QD

+

BM

S-6

5003

2 20

0 m

g Q

12h

Geo

Mea

n (

CV

)N

orm

aliz

ed t

o 6

00-m

g D

ose

GM

R (

90%

CI)

AU

C(T

AU

) –

AM

1063

(58

)92

3 (4

4)0.

868

(0.7

26, 1

.038

)

Cm

ax–

AM

420

(48)

247

(64)

0.58

1 (0

.446

, 0.7

58)

Cm

in–

AM

10.9

(55

)19

.3 (

28)

1.75

6 (1

.420

, 2.1

71)

AU

C(T

AU

) –

PM

6104

(49

)18

00 (

43)

0.29

(0.

23, 0

.39)

Cm

ax–

PM

2257

(51

)42

8 (9

3)0.

19 (

0.12

, 0.2

9)

Cm

in–

PM

55.7

(50

)45

.5 (

50)

0.82

(0.

63, 1

.07)

DIS

CU

SS

ION

The

PK

inte

ract

ion

obse

rved

in th

e no

nclin

ical

spe

cies

was

not

obs

erve

d in

nor

mal

he

alth

y su

bjec

tsE

xpos

ures

to B

MS

-650

032

appe

ar g

reat

er a

fter

the

PM

dos

e re

lativ

e to

the

AM

dos

e.T

his

incr

ease

in e

xpos

ure

appe

ars

to b

e do

se d

epen

dent

–A

UC

(TA

U)↑

~6-

fold

afte

r P

M d

ose

of 6

00 m

g Q

12h

–A

UC

(TA

U)↑

~2-

fold

afte

r P

M d

ose

of 2

00 m

g Q

12h

–In

a p

revi

ous

phas

e 1

stud

y, n

o di

urna

l var

iatio

n ob

serv

ed w

ith 1

00 m

g Q

12h

Diu

rnal

var

iatio

n ob

serv

ed w

as li

kely

due

to fo

od e

ffect

–P

M d

ose

adm

inis

tere

d 2

hour

s af

ter

a st

anda

rd m

eal

–D

ata

from

a fo

od-e

ffect

stu

dy s

ugge

st a

hig

h-fa

t mea

l inc

reas

es A

UC

of

BM

S-6

5003

2 60

0-m

g ta

blet

~12

-fol

dT

he m

ultip

le-a

scen

ding

-dos

e an

d pr

oof-

of-c

once

pt s

tudi

es fo

r B

MS

-650

032

wer

e do

sed

in th

e sa

me

man

ner;

ther

efor

e, th

e in

crea

sed

PM

exp

osur

es h

ave

been

fact

ored

in

to th

e do

se s

elec

tion

and

safe

ty e

valu

atio

n

Saf

ety

Adm

inis

trat

ion

of 7

day

s of

trea

tmen

t with

BM

S-6

5003

2 60

0 m

g Q

12h

(Tre

atm

ent A

) or

BM

S-7

9005

2 60

mg

QD

(T

reat

men

t B),

follo

wed

by

14 d

ays

of c

ombi

natio

n tr

eatm

ent w

ith B

MS

-650

032

200

mg

Q12

h +

BM

S-7

9005

2 30

mg

QD

(T

reat

men

t C),

w

as w

ell-t

oler

ated

by

the

heal

thy

subj

ects

in th

is s

tudy

The

re w

ere

no d

eath

sO

ne (

1) s

erio

us a

dver

se e

vent

was

rep

orte

d. O

ne (

1) s

ubje

ct d

isco

ntin

ued

the

stud

y as

per

the

prot

ocol

sto

ppin

g ru

les

due

to a

n in

crea

se in

AS

T; t

he a

dver

se e

vent

(A

E)

was

acc

ompa

nied

by

an A

E o

f inc

reas

e in

blo

od c

reat

ine

kina

se, w

hich

was

co

nsid

ered

ser

ious

. The

se la

bora

tory

cha

nges

wer

e no

t ass

ocia

ted

with

mya

lgia

or

any

mus

culo

skel

etal

AE

s, a

nd w

ere

cons

iste

nt w

ith e

xerc

ise-

rela

ted

chan

ges.

The

AE

re

solv

ed fo

llow

ing

disc

ontin

uatio

n of

stu

dy d

rug

Mos

t AE

sw

ere

mild

in in

tens

ity, a

nd n

o A

E w

as a

sses

sed

as s

ever

e or

ver

y se

vere

in

inte

nsity

Gas

troi

ntes

tinal

AE

sw

ere

the

mos

t com

mon

trea

tmen

t-re

late

d A

Es

with

all

trea

tmen

ts,

and

all r

elat

ed A

Es

wer

e m

ild in

inte

nsity

No

safe

ty is

sues

em

erge

d fr

om th

e ev

alua

tion

of th

e cl

inic

al la

bora

tory

, vita

l sig

n,

EC

G, o

r ph

ysic

al e

xam

inat

ion

data

AS

T =

asp

arta

team

inot

rans

fera

se.

BM

S-7

9005

2 C

urr

ent

Stu

dy

(Stu

dy

AI4

4700

9) v

sH

isto

rica

l Dat

a F

rom

H

ealt

hy

Vo

lun

teer

s (S

tud

y A

I444

003)

0

200

400

600

800

1000

1200

04

812

1620

24

Tim

e (h

)

Mean [BMS-790052] (ng/mL)

Stu

dy A

I447

009:

BM

S-7

9005

2 30

mg

QD

+ B

MS

-650

032

200

mg

Q12

h (n

=26)

Stu

dy A

I444

003:

BM

S-7

9005

2 30

mg

QD

(n=

6)

Whe

n th

e 20

0 m

g Q

12h

expo

sure

s w

ere

norm

aliz

ed to

a d

ose

of 6

00 m

g Q

12h,

B

MS

-650

032

AU

C(T

AU

)-AM

was

sim

ilar

to 6

00 m

g Q

12h

alon

e; A

UC

(TA

U)-P

M w

as ~

70%

lo

wer

, Cm

ax-A

M a

nd P

M w

ere

both

low

er, C

min-A

M w

as h

ighe

r, a

nd C

min-P

M w

as

com

para

ble

to 6

00 m

g Q

12h

adm

inis

tere

d al

one

BM

S-6

5003

2 C

urr

ent

Stu

dy

(AI4

4700

9) v

sH

isto

rica

l Dat

a (A

I447

003)

020406080100

120

140

160

180

200

02

46

810

12

Tim

e (h

)

Mean [BMS-650032] (ng/mL)

AI4

4700

9: B

MS

-650

032

200

mg

Q12

h +

BM

S-7

9005

2 30

mg

QD

(n=

26)

AI4

4700

3: B

MS

-650

032

200

mg

Q12

h (n

=6)

BM

S-6

5003

2 C

urr

ent

Stu

dy

(AI4

4700

9) v

sH

isto

rica

l Dat

a (A

I447

003)

BM

S-6

5003

2 20

0 m

g Q

12h

PK

Par

amet

erA

I447

009

(BM

S-7

9005

2 +

BM

S-6

5003

2)G

eo M

ean

(C

V)

AI4

4700

3 (B

MS

-790

052

Alo

ne)

Geo

Mea

n (

CV

)G

MR

(90

% C

I)

AU

C(T

AU

) –

AM

308

(44)

300

(39)

1.02

5 (0

.734

, 1.4

33)

Cm

ax)625.1 ,375.0( 539.0

)26( 88)46( 28

MA

–

C12

6.44

(28

)8.

44 (

60)

0.76

3 (0

.579

, 1.0

06)

Exp

osur

es o

f BM

S-6

5003

2 20

0 m

g Q

12h

whe

n co

adm

inis

tere

dw

ith B

MS

-790

052

30 m

g w

ere

com

para

ble

to h

isto

rical

dat

a fo

r B

MS

-650

032

200

mg

Q12

h ad

min

iste

red

alon

e

RE

SU

LT

S

827

CO

NC

LU

SIO

NS

FINAL