UPDATE ON JUPITER I AND II CLINICAL TRIALSWITH THE SORIN CARBOSTENT TRACROLIMUS

ELUTING STENT

GB Danzi, MDOspedale Maggiore Policlinico

University of MilanMilan - Italy

JANUS CARBOSTENT: THE PLATFORM

2) MIRROR POLISHING

1) CLOSED CELLARCHITECTURE

THROMBORESISTANCE

Distinctive FeatureDistinctive FeatureDistinctive Feature

6 years of clinical use

3) CARBOFILM COATING BIO- & HEMOCOMPATIBILITY

BenefitBenefitBenefit

HOMOGENEOUS EXPANSION

Stent crosssection

Reservoirs on theexternal surface

Strut crosssection

THE EXTERNAL SURFACE OF JANUS CARBOSTENT IS SUITABLY GROOVED TO PROVIDE DEEP RESERVOIRS FOR THE DRUG

AFTER THE RESERVOIRS ARE REALIZED THE WHOLE SURFACE OF THE STENT IS COATED WITH CARBOFILM™

IntegralCarbofilm™

coating

RESERVOIRS ON THE SURFACE TO LOAD THE DRUG

JANUS JANUS CarbostentCarbostent

Deep drug reservoirson the external surface

Endothelial cells

Smooth muscle cells

VESSEL WALL

BLOOD

JANUS CARBOSTENT RELEASING MECHANISMJANUS CARBOSTENT RELEASING MECHANISM

• DEEP SCULPTURES ON THE OUTER STENT SURFACE CONTAIN AND RELEASE THE DRUG ONLY TOWARDS THE VESSEL WALL

• NO DRUG IS LOST INTO THE BLOOD STREAM

STENT STRUTCROSS SECTION

Drug releasingSCULPTURE

JANUS CARBOSTENT - The DRUG

Tacrolimus is the active ingredient of two pharmaceutical products registered in all the main countries of the world: the immunosuppressant Prograf®, used in the treatment of patients after kidney or liver transplantation, and the Protopic®, used in the treatment of atopic dermatitis.

The first drug which has been selected and tested in combination with Janus Carbostent is TacrolimusTacrolimus (FK 506)(FK 506),produced by Fujisawa Pharmaceutical Co. (Japan).

Streptomyces Tsukubaensis

UPDATE

on

JUPITER I

Jupiter I:: StudyStudy DesignDesign

α phase

Clinical registry≥ 50 patients

Interim analysis

at 1 month

“Safety” evaluation

Clinical evaluation randomized 1:1

multicenterdouble blind

Investig. & Core-Lab

β phaseJANUS≥ 50 patients

TECNIC (control)≥ 50 patients

Clinical, angiographicand IVUS follow-up at

6 months

Clinical follow-up at 12 and 24

months

Follow-up at 1, 6, 12 and 24 months

•• 1 1 monthmonth: : ClinicalClinical

•• 6 6 monthsmonths: : ClinicalClinical, , angiographicangiographic and IVUSand IVUS

•• 12 12 monthsmonths: : ClinicalClinical

•• 24 24 monthsmonths: : ClinicalClinical

Jupiter I study - β phase

Jupiter I -- β: Study UpdateUpdate

32

102

3719 24

17

50

19

11010

19

52

110

271418

0

20

40

60

80

100

120

Monzin

o-Mila

no

Poliam

bulan

za-B

rescia

San Pietro

FBF-Rom

a

Osped

ale de

gli Infe

rmi-R

imini

Hespe

ria H

ospit

al-Mod

ena

Osped

ale Ferr

arotto-

Catania

TOTAL

# pa

tient

s Nb patientsGroup AGroup B

Enrolment completed on December 2004

32

102

3719 24

17

50

19

11010

19

52

110

271418

0

20

40

60

80

100

120

Monzin

o-Mila

no

Poliam

bulan

za-B

rescia

San Pietro

FBF-Rom

a

Osped

ale de

gli Infe

rmi-R

imini

Hespe

ria H

ospit

al-Mod

ena

Osped

ale Ferr

arotto-

Catania

TOTAL

# pa

tient

s

Nb patientsGroup AGroup B

Jupiter I study - β phase

GROUP A GROUP B P P valuevalueN° of enrolled pts (102) 50 52

N° of available pts (92) 46 49

Male 89.1% 79.6% .203Age (yrs) 64.6 ± 11.6 64.0 ± 10.4 .788

Clinical Status .436Asymptomatic 6.5% (3 pts) 8.2% (4 pts)Silent Ischemia 8.7% (4 pts) 8.2% (4 pts)Stable Angina 60.9% (28 pts) 42.8% (21 pts)Unstable Angina 15.2% (7 pts) 28.6% (14 pts)MI 8.7% (4 pts) 12.2% (6 pts)

Jupiter I - β: Base-Line Clinical CharacteristicsJupiter I study - β phase

Unstable angina

28,6

14,3

0 7,1

28,6

50,0

14,2

0

28,6 28,6

0

20

40

60

80

100

1B 2A 2B 2C 3B

GROUP AGROUP B

%

21,420,0

50,0 50,0

21,430,0

7,20

0

20

40

60

80

100

I II III IV

GROUP AGROUP B

Stable angina

%

p=.619

p=.478

Jupiter I - β: Base-Line Clinical Characteristics

Jupiter I study - β phase

GROUP A GROUP B P value

Risk factors 46 49

Smokers 37.0% (17 pts) 42.9% (21 pts) .557

Diabetes 17.4% (8 pts) 28.6% (14 pts) .197

ID Diabetes 4.3% (2 pts) 2.0% (1 pts) .520

NID Diabetes 13.0% (6 pts) 26.5% (13 pts) .101

Hypertension 69.6% (32 pts) 59.2% (29 pts) .291

Hypercholesterolemia 63.0% (29 pts) 79.6% (39 pts) .074

Family history of CAD 21.7% (10 pts) 22.4% (11 pts) .934

Jupiter I - β: Base-Line Clinical Characteristics

Jupiter I study - β phase

Jupiter I - β: Target lesion characteristics

GROUP A GROUP B P value N° of available lesions (103) 50 53

De Novo 100% 100%

Lesion morphology .942Concentric 46.0% (23/50 les) 45.3% (24/53 les)Eccentric 54.0% (27/50 les) 54.7% (29/53 les)

Calcification 10.0% (5/50 les) 9.4% (5/53 les) .923

Tortuosity 12.0% (6/50 les) 3.8% (2/53 les) .119

Bifurcation 0% 0%

Ostial Lesion 0% 0%

Total Chronic Occlusion 2.0% (1/50 les) 0% .301

Jupiter I study - β phase

2,05,9

38,033,3

50,045,1

10,015,7

0

20

40

60

80

100

A B1 B2 C

GROUP AGROUP B

Lesion Type

%

p=.598

Jupiter I - β: Target lesion characteristics

Jupiter I study - β phase

% 40,034,0

22,0 22,6

38,043,4

0,0

20,0

40,0

60,0

80,0

100,0

LAD LCX RCA

Group AGroup B

Target Vessels p=.801

Jupiter I - β: Target lesion characteristics

Jupiter I study - β phase

Jupiter I - β : Procedural angiographic data

15.1

3.11 0.843.22 0.76 2.79

73.2

3.27 2.91

7.7

76.0

15.1

3.11

8.7

0

20

40

60

80

100

Les.length

PRE (mm)

RVD PRE(mm)

RVDPOST(mm)

MLD PRE(mm)

MLDPOST(mm)

D.S. PRE(%)

D.S. POST(%)

Group AGroup B

Jupiter I study - β phase

GROUP A GROUP B P value Stenting procedure 50 53 .923

Direct stenting 10.0% (5/50 les) 9.4% (5/53 les)

Predilation 90.0% (45/50 les) 90.6% (48/53 les)

N° stent / lesion 1.08 1.00

Max. stent depl. pressure (atm) 15.29 ± 2.86 15.36 ± 2.59 .893

Postdilation 52.0% (26/50 les) 50.9% (27/53 les) .915

Dissection 0% 0%

Procedural success 100% 100%

TIMI flow 3 100% 100%

Residual stenosis <20% 100% 100%

Jupiter I - β : Procedural dataJupiter I study - β phase

GROUP A GROUP B50 52

MACEDeath 0% 0%MI 0% 3.8% (2)TLR 0% 0%

CABG _ _Re-PTCA _ _Re-PTCA + Stent _ _

Total events 0% 3.8% (2)

Acute Thrombosis 0% 0%

Jupiter I - β : Preliminary in-hospital MACE

Jupiter I study - β phase

Jupiter I - β : Preliminary 30-day follow-up

GROUP A GROUP B50 52

MACEDeath 0% 0%MI 0% 3.8% (2)TLR 0% 0%

CABG _ _Re-PTCA _ _Re-PTCA + Stent _ _

Total events 0% 3.8% (2)

Sub-acute Thrombosis 0% 0%

Jupiter I study - β phase

The 6-month follow-up results will be available on October 2005

JUPITER II preliminary

clinical data

Jupiter II study

Clinical evaluation randomized 1:1

16 centers in Europedouble blind

(Investigator & Core-Lab)

JANUS150 + 10% drop-out = 165 pts

TECNIC150 + 10% drop-out = 165 pts

Follow-up• 1 month: Clinical

• 6 months: Clinical, Angiographic

• 12 months: Clinical

• 24 months: Clinical

Jupiter II: Study Design with high dose: 2.3µg/mm2

Jupiter II study

Profile Increased by Polymer CoatingProfile Increased by Polymer Coating

Polymer coatings used as drug carriers for DES contribute to increase the device profile in comparison to the platform stents

1.12 mm*1.30 mm*

* * CrossingCrossing profilesprofiles measuredmeasured accordingaccording toto ASTM F2081ASTM F2081--0101

BxBx SonicSonic™™(3.0 x 18 mm)(3.0 x 18 mm)

CypherCypher SelectSelect™™(3.0 x 18 mm)(3.0 x 18 mm)

No Profile Increase AvoidingNo Profile Increase AvoidingA Polymer Coating A Polymer Coating

1.08 mm* 1.08 mm*

* * CrossingCrossing profilesprofiles measuredmeasured accordingaccording toto ASTM F2081ASTM F2081--0101

TecnicTecnic CarbostentCarbostent™™(3.0 x 15 mm)(3.0 x 15 mm)

JanusJanus CarbostentCarbostent™™(3.0 x 15 mm)(3.0 x 15 mm)

Polymer Coating FragilityPolymer Coating FragilityThe polymer coatings and matrices used as drug carriers for DES are relatively soft and fragile. During stent delivery and implant they are exposed to the risk of scratches and

peeling, especially when the Direct Stenting technique is used.is used.

100 X30 X

30 X 100 X

TaxusTaxus

CypherCypher

After 1 After 1 ““round tripround trip”” through the through the guiding guiding cathetercatheter and and intointo a a diseaseddiseased coronarycoronary arteryartery

Integrity of Incorporated Drug

JANUS JANUS CarbostentCarbostent has no polymeric coating on its surface.has no polymeric coating on its surface.The drug is deposited directly into the reservoirs created on thThe drug is deposited directly into the reservoirs created on the e abluminalabluminal stent surface stent surface

and is protected during delivery, even when the and is protected during delivery, even when the Direct Stenting technique Direct Stenting technique is used.is used.

Janus

30 X

After 1 After 1 ““round tripround trip”” through the through the guiding guiding cathetercatheter and and intointo a a diseaseddiseased coronarycoronary arteryartery

Jupiter II: Participating centers

Prof. Macaya - MadridSPAIN (1)

Dr. Cremonesi – CotignolaITALY (1)Prof. Di Mario, Prof. Ilsey - LondonU.K. (2)

Prof.Neumann, Prof. Bestehorn – Bad Krozingen

Dr. Hoffmann - BerlinDr. Hempel - Dresden

GERMANY (3)

Dr. Morice (PI) – MassyProf. Carrié - Toulouse

FRANCE (2)

Dr. De Bruyne, Dr. Wijns - AalstDr. Verheye – Antwerp

Dr. Dubois - Leuven

BELGIUM (3)

Prof. Amann - ZurichSWITZERLAND (1)Prof. Pachinger - InnsbruckAUSTRIA (1)

Dr. Aengevaeren-NijmegenProf. Serruys - Rotterdam

Dr. De Winter - Amsterdam

THE NETHERLANDS (3)

INVESTIGATORCOUNTRY

Jupiter II study

Jupiter II: Enrolment

154 10 16

0 3 2 116 10 5

3515 5 9 18 20 21

0 3 0 1 1 10 9 3 2

309

34 39 42

0 6 2 5 8 3

332

19 2114 9

30

166

14

166

24251919 2

65

0

40

80

120

160

200

240

280

320

Bad K

rozing

enAals

tInn

sbruc

kMas

syNijm

egen

Madrid

Tou

louse

Zurich

Lond

on B.

Lond

on H

.Coti

gnola

Rotterd

amAntw

erpLe

uven

Amsterda

mBerl

inDres

den

TOTAL

Group AGroup B TOTAL

Jupiter II study

Enrolment Completed as for Dec. 2004

Jupiter II: Primary Endpoint

Assessment of in-stent and peri-stent “Late Lumen Loss (LLL)” at 6 month follow-up by Quantitative Coronary Angiography (QCA)

In-stent: measurement within the stented areaPeri-stent: measurement within the stented segment and within 5 mm proximal and distal to the stent edges

Peri-stent5 mm 5 mm

in stent

Jupiter II study

GROUP A GROUP B p valueN° of enrolled pts (332) 166 166

N° of available pts (272) 159 159Male 75.5% 74.8% .8967Age (yrs) 63.7 ± 10.0 63.7 ± 9.7 .9773

Clinical StatusAsymptomatic 5.7% (9 pts) 4.4% (7 pts) .6079Silent Ischemia 8.2% (13 pts) 6.9% (11 pts) .6711Stable Angina 66.0% (103 pts) 62.9% (100 pts) .5580Unstable Angina 15.1% (24 pts) 17.6% (28 pts) .5442MI 5.0% (8 pts) 8.2% (13 pts) .2589

CADSingle vessel disease 61.6% (98 pts) 59.8% (95 pts) .7305

Multivessel disease 38.4% (61 pts) 40.2% (64 pts) .7305

Jupiter II: Base-Line Clinical CharacteristicsJupiter II study

GROUP A GROUP B p value

Risk factors 159 159

Smokers 38.4% (61 pts) 44.0% (70 pts) .3052

Diabetes 19.5% (31 pts) 17.6% (28 pts) .6652ID Diabetes 6.3% (10 pts) 2.5% (4 pts) .1698NID Diabetes 13.2% (21 pts) 15.1% (24 pts) .6293

Hypertension 62.9% (100 pts) 57.2% (91 pts) .3028

Hypercholesterolemia 69.2% (110 pts) 67.3% (107 pts) .7178

Family history of CAD 7.7% (44 pts) 28.9% (46 pts) .8034

Other Pathology 6.9% (11 pts) 9.4% (15 pts) .4130

Jupiter II: Base-Line Clinical CharacteristicsJupiter II study

GROUP A GROUP B p value

N° of lesions (365) 182 183De Novo 98.9% (178/180 les) 99.5% (181/182 les) .6219

Concentric 53.4% (87/163 les) 47.7% (83/174 les) .2979

Eccentric 46.6% (76/163 les) 52.3% (91/174 les) .2979

Calcification 17.2% (31/180 les) 21.4% (39/182 les) .3110

Tortuosity 6.7% (12/180 les) 13.1% (24/183 les) .0399

Bifurcation 0% 2.7% (5/183 les) .0608

Ostial Lesion 0.6% (1/180 les) 1.1% (2/183 les) 1.000

Total Chronic Occlusion 0% 1.1% (2/183 les) .4987

Jupiter II: Target lesions CharacteristicsJupiter II study

19,3 17,8

54,7

47,9

23,629,5

2,5 4,9

0

20

40

60

80

100

A B1 B2 C

GROUP AGROUP B

Lesion Type

%

Jupiter II: Target lesions Characteristics

p=0.3854

Jupiter II study

%37,9

30,128,0 27,9

34,1

41,5

0 0,50

20

40

60

80

100

LAD LCX RCA LM

Group AGroup B

Target Vessels

Jupiter II: Target lesions Characteristics

p=0.3018

Jupiter II study

Jupiter II: Procedural angiographic data

3.02 1.062.98 1.03 2.97

11.7

73.5

3.07 2.91

5.2

75.2

12.43.07

4.2

0

20

40

60

80

100

Les.lengthPRE(mm)

RVDPRE(mm)

RVDPOST(mm)

MLDPRE(mm)

MLDPOST(mm)

D.S.PRE (%)

D.S.POST

(%)

Group AGroup B

Jupiter II study

GROUP A GROUP B p valueStenting procedure 182 183Direct stenting 82.4% (150 les) 72.7% (133 les) .0258

Postdilation after direct stenting 15.3% (23/150 les) 14.3% (19/133 les)

N° stent / lesion 1.03 1.08MIP (atm) 13.74 ± 2.93 13.62 ± 3.00 .6942

Postdilation 16.9% (29/172 les) 18.4% (33/179 les) .6989

Dissection 1.1% (2/182 les) 3.8% (7/183 les) .1743

Procedural success 99.4% (170/171 les) 99.4% (172/173 les) 1.000

TIMI flow 3 100% 100%

Residual stenosis >20% 0.6% (1/1) 0.6% (1/183) 1.000

Jupiter II: Procedural dataJupiter II study

32.4

8.5

2.7

14.1

7.6

1.56.1

9.06.9

4.3

16.519.7

27.3

5.6

13.6

24.2

0.0

10.0

20.0

30.0

40.0

3.0x1

2 mm

3.0x1

5 mm

3.0x1

9 mm

3.0x2

5 mm

3.5x1

2 mm

3.5x1

5 mm

3.5x1

9 mm

3.5x2

5 mm

%

Group A

Group B

Stent size distribution

Jupiter II: Procedural dataJupiter II study

GROUP A GROUP B* p value159 159

MACEDeath 0% 0%MI 0.63%(1) 0.63% (1) 1.0000TLR 1.26% (2) 0% .3260

CABG 0% 0%

Re-PTCA 0.63% (1) 0%

Re-PTCA + Stent 0.63% (1) 0%

Total events 1.89% (3) 0.63% (1) .3812

Acute Thrombosis 0% 0%

Jupiter II: Preliminary in-hospital MACE

* 1 protocol deviation censored

Jupiter II study

Jupiter II: Preliminary 30-day follow-up*GROUP A GROUP B p value

Clinical status 159 159

MACEDeath 0% 0%MI 0.8% 0% .3772TLR 0% 0%

CABG 0% 0%

Re-PTCA 0% 0%

Re-PTCA + Stent 0% 0%

Total events 0.8%(1) 0% .3772

Sub-acute Thrombosis 1.6% (2) 0% .3246

* Clinical events not yet adjudicated by Critical Event Committee

Jupiter II study

The 6-month follow-up results will be available on October 2005

Conclusion: Clinical Studies

• Initial clinical outcomes are showing a positive performance in term of MACE, incidence of acute and subacute thrombosis in bothgroups;

• The preliminary Jupiter II 30-day results demonstrate low rate of clinical events in both groups confirming at short term that the two stents in evaluation have a comparable clinical safety (MACE and Thrombosis);

• Janus is the latest innovative DES platform, designed for resolving major limitations of current DES with polymer coatings.

Jupiter II study

DIABETes and drug Eluting Stent

The DIABETES III Trial

DIABETES III

Diabetes IIISTUDY DESIGN:

Multicenter:

• Madrid: Hospital Clinico San Carlos, Prof. Macaya, Dr. Sabaté (PIs)

• Barcelona: Hospital de Bellvitge, Dr. Cequier

• Murcia: Hospital Virgen de Arrixaca, Dr. Valdes

Spanish Prospective Trial (80 pts will be enrolled)

START OF THE STUDY: December 2004

AIM OF THE STUDY: To evaluate the efficacy of Janus Carbostent on the

inhibition of neointimal proliferation, assessed by QCA at 9 month follow-up, in

diabetic patients. The obtained results will be compared to an historical cohort

treated with bare metal stent (DIABETES I trial)

DIABETES III

PRIMARY ENDPOINT:

• Late Lumen Loss (in-stent + edges) by QCA at 9 month f-up

SECONDARY ENDPOINTS:

• In-stent + edges neointimal hyperplasia area by IVUS at 9 month f-up

• Binary restenosis rate, MLD and mean luminal diameter at 9-month f-up

• MACE at 1, 9, 12 and 24 month f-up

• Occurrence of complications attributable to DES: late stent thrombosis,

edge effect, late stent malapposition, coronary aneurysm

Diabetes IIIDIABETES III

Diabetes III

Enrolment started in December 2004

12 16

64

36

0

40

80

Madrid Barcelona Murcia Total

DIABETES III

eJANUS

eJANUS

eJanus

STUDY DESIGN:European, Multicenter (100-200), Prospective Registry Based on electronic CRFs

START OF THE STUDY: November 2004

AIM OF THE STUDY:Assessment of clinical performances of Janus Carbostent in the treatment of de novo or restenotic lesions in “real world” population

STUDY POPULATION:All “real world” patients (2500 pts) with stable/unstable angina, documented ischemia or AMI who are scheduled to undergo coronaryangioplasty of de novo or restenotic lesion(s) in native coronary arteries

eJANUS

eJanusPRIMARY ENDPOINTS:

• Incidence of MACE within discharge, 30 days, 6, 12 & 24 months

• Thrombosis rate within discharge, 30 days, 6, 12 & 24 months (acute, sub-acute

& late thrombosis)

• Clinical performances of Janus Carbostent, during implant procedure

SECONDARY ENDPOINT:

• Clinically driven TLR at 6 months

eJANUS

eJanus Enrolment UpdateeJANUS

Enrolment started in November 2004

12

178

498

5

148119

2195

297

445

050

100150200250300350400450500

nov-04 dec-04 jan-05 feb-05 mar-05 apr-05

# PT

S ptscumulative

5 4 12

98

178

148

020406080

100120140160180200

NOV DEC JAN FEB MAR APR

2004 2005

AUSTRIA

FRANCE

ITALY

NETHERLANDS

SPAIN

UNITED KINGDOM

TOTAL

SORIN JANUS CARBOSTENT

FUTURE DEVELOPMENTS

POSSIBILITY TO REALIZE DIFFERENT RESERVOIRS

“V” shaped reservoirs

“U” shaped reservoirs

The shape and size of the reservoirs can be selected in order to:

1) CONTAIN DIFFERENT AMOUNT OF DRUG

2) ADJUST THE RELEASE KINETIC

Different shape reservoirs

0102030405060708090

0 2 4 6 8 10 12 14 16 18 20 22 24

Time (h)

% d

rug

rele

ased

V shaped reservoirU shaped reservoir

EFFECT OF THE RESERVOIR SHAPE ON RELEASE KINETIC

RESERVOIR FILLEDWITH ONE DRUG

ONE DRUG +

POLYMER COVER FOR SLOWER RELEASE

THICKER POLYMERCOVER FOR EVENSLOWER RELEASE

RESERVOIR FILLED WITH A POLYMER MATRIX

CONTAINING THE DRUG

TWO POLYMERMATRICES CONTAINING

TWO DIFFERENT DRUGS

TWO POLYMERMATRICES CONTAINING

TWO DIFFERENT DRUGS+

TWO POLYMER COVERS

Carriers: a choice not an obligation.

With Janus platform no additional carrier is strictly required, but the widest choice of drug formulations and excipients can be used to realizemore sophisticated release profiles.

SEM images of Sorin proprietarycarriers under evaluation

Porous matrix with top coat Porous matrix Tubular matrix

Thin polymeric bilayermetallografic section

Drug: tacrolimusTop coating: PVA/AA

Porous matrixDrug: paclitaxel

Porous film: PMMA/AA 90:10

Porous matrixDrug: tacrolimus

Porous film: PMMA/AA 90:10

Thin polymeric bilayermetallografic section

Drug: paclitaxelTop coating: PVA/AA

Drug

Top coat

Drug

Top coat

INFLUENCE OF POLYMER MATRICES ON THE RELEASE KINETIC

LONGITUDINAL DOSE DISTRIBUTIONLONGITUDINAL DOSE DISTRIBUTION

Variable dose distribution along the longitudinal axis of the stentcan be achieved filling the reservoirs with different amount of drug

Homogeneous distributionHomogeneous distribution

Two levels distributionTwo levels distribution

Three levels distributionThree levels distribution

(Dose level)

LONGITUDINAL DRUG / DOSE DISTRIBUTIONLONGITUDINAL DRUG / DOSE DISTRIBUTION

Suitable amount of different drugs can be loaded selectively alongthe longitudinal axis of the stent to provide synergic therapeutic effects

Homogeneous distributionof two different drugs

Homogeneous distributionof two different drugs

Two different drugs intwo different areas

Two different drugs intwo different areas

Three levels distributionThree levels distribution

(Dose level)