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Experiment 1 – Graded Dose-Response Curve B1 24 July 2007
Outline • • • •
Introduction Objectives Materials and Methods Results Expected Actual
• Discussion • Conclusion
DOSE-EFFECT RELATIONSHIP • The intensity and duration of a drug’s effects are a function of the drug dose and drug concentration at the effect site • X-axis – drug concentration • Y-axis – response
DOSE-RESPONSE CURVE
TYPES OF DOSE-RESPONSE RELATIONSHIPS GRADED DOSE-RESPONSE
QUANTAL DOSE-RESPONSE
• Continuous scale (↑dose → ↑ effect)
• All-or-none pharmacologic effect
• Measured in a single biologic unit
• Population studies
• Relates dose to intensity of effect
• Relates dose to frequency of effect
DOSE-RESPONSE CURVE POTENCY
MAXIMAL EFFICACY
• Relative position of the doseresponse curve along the dose axis
• Determined principally by the properties of the drug and its receptor-effector system • Reflected in the plateau of the dose-response curve • Shows the clinical effectiveness of a drug
OBJECTIVES • GENERAL To compare the anti-inflammatory properties of aspirin, paracetamol, celecoxib, and prednisone using the grade dose-response curve.
• SPECIFIC To determine the percent (%) response to inhibition of inflammation with aspirin, paracetamol, celecoxib and prednisone on Carrageenan-induced foot edema of rats. To compare the relative potency and maximal efficacy of aspirin, paracetamol, celecoxib, and prednisone antiinflammatory using the graded dose-response curve.
MATERIALS AND METHODS • 12 week old rats • Phlogistic Agent (Carrageenan) • Gavage Tubes, Syringe • Mercury Set-up • Drugs ▫ ▫ ▫ ▫
Paracetamol Aspirin Celecoxib Prednisone
Doses : per 200 g rat
Carrageenan • phlogistic agent of choice for testing antiinflammatory agents both steroidal and nonsteroidal • is a mucopolysaccharide derived from Irish sea moss, Chondrus
Katzung. Basic and Clinical Pharmacology, 10th ed.
COX-2 Inhibitors Pathway
CELECOX IB
PARACETAMOL • Weak COX-1 and COX-2 inhibitor due to
activity in the brain • No significant anti-inflammatory effects; more on analgesic effects RECENT STUDIES:
• selective inhibition of the enzyme COX-3 in the brain and spinal cord
ASPIRIN • Anti-platelet (160-325mg/day) ▫ Inhibits synthesis of TXA
• Antipyretic (325-650mg/4 hrs) ▫ Inhibit PGE2
• Anti inflammatory (4-6gday) ▫ COX-1 and COX-2
CELECOXIB • Selective COX-2 inhibitor ▫ Effective anti-inflammatory drug
PREDNISONE • Glucocorticoids • anti-inflammatory and immunosuppressive effect • inhibits Phospholipase A2 • COX-2 inhibiting effects as the NSAIDs
% difference (inflammation) = (reading after - reading before injection of phlogistic agent) reading before injection of phlogistic agent % inhibition = (reading before injection of phlogistic agent - reading after ) reading before injection of phlogistic agent
RESULTS Expected ▫ Anti-inflammatory property (Efficacy) Prednisone > Celecoxib =Aspirin > Paracetamol
▫ Potency Prednisone > Celecoxib > Paracetamol > Asprin
RESULTS Actual ▫ Anti-inflammatory property (Efficacy) Celecoxib =Aspirin > Prednisone> Paracetamol
▫ Potency Prednisone > Celecoxib > Paracetamol = Asprin
SOURCES OF ERROR • • • • •
Variability in handling Initial inflammation Drug was not fully dissolved in NSS Spillage during gavage feeding Measurement of foot volume Mercury level Reader variability
Graded-Dose Response Curve SECTION A Paracetamol
Graded-Dose Response Curve SECTION B
Foot Volume
Preparati on: 500 mg tablet 0.5 mg / 200 Doses: gm rat
Before
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.002 0.003 0.002 0.002 0.002 0.001 0.001
Caragee nan
0.002 0.002 0.001 0.003 0.004 0.003 0.004 0.008
Aspirin 1 hr
0.005 0.006 0.007 0.004 0.005 0.005 0.004 0.005
2 hrs 3 hrs
0.004 0.005 0.006 0.004 0.002 0.004 0.005 0.004
0.004 0.005 0.007 0.005 0.006 0.005 0.007 0.003
1.6 mg / 200 gm rat
Foot Volume
Preparati on: 200 mg tablet 0.5 mg / 200 Doses: gm rat
Before
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.002 0.001 0.003 0.001 0.001 0.002 0.001
Carageen an 1 hr
0.002 0.002 0.003 0.003 0.001 0.001 0.005 0.001
0.002 0.005 0.001 0.002 0.003 0.008 0.002 0.001
2 hrs 3 hrs
0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
0.004 0.003 0.001 0.001 0.002 0.003 0.001 0.001
1.6 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.002 0.002 0.002 0.002 0.001 0.002 0.001
0.003 0.005 0.004 0.004 0.004 0.001 0.003 0.004
0.006 0.005 0.005 0.004 0.005 0.003 0.006 0.007
0.002 0.002 0.005 0.005 0.006 0.005 0.004 0.005
0.007 0.004 0.005 0.004 0.005 0.005 0.003 0.008
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.004 0.003 0.004 0.002 0.003 0.002 0.003 0.003
0.002 0.003 0.004 0.003 0.005 0.005 0.004 0.005
0.004 0.002 0.004 0.001 0.001 0.003 0.003 0.001
0.003 0.002 0.002 0.001 0.002 0.003 0.003 0.003
0.004 0.004 0.002 0.001 0.002 0.001 0.001 0.001
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.001 0.001 0.001 0.001 0.001 0.002 0.001 0.001
0.001 0.003 0.002 0.006 0.004 0.002 0.006 0.002
0.003 0.003 0.005 0.007 0.003 0.001 0.006 0.004
0.004 0.004 0.007 0.004 0.003 0.003 0.005 0.002
0.003 0.006 0.005 0.005 0.005 0.004 0.004 0.006
5 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.003 0.002 0.003 0.002 0.005 0.006 0.004
0.003 0.003 0.003 0.002 0.003 0.003 0.007 0.005
0.002 0.002 0.002 0.002 0.005 0.003 0.005 0.002
0.002 0.001 0.001 0.001 0.005 0.004 0.004 0.003
0.002 0.002 0.001 0.001 0.001 0.002 0.003 0.002
16 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.001 0.002 0.001 0.002 0.001 0.001 0.001 0.001
0.001 0.004 0.002 0.002 0.004 0.003 0.002 0.003
0.004 0.005 0.003 0.005 0.004 0.005 0.007 0.005
0.008 0.004 0.005 0.004 0.005 0.006 0.006 0.004
0.005 0.005 0.007 0.005 0.005 0.003 0.004 0.005
0.003 0.001 0.004 0.002 0.002 0.001 0.001 0.001
0.001 0.002 0.001 0.001 0.002 0.001 0.001 0.001
0.001 0.007 0.001 0.004 0.001 0.001 0.001 0.001
0.001 0.004 0.001 0.001 0.002 0.001 0.002 0.004
0.001 0.001 0.001 0.001 0.001 0.008 0.001 0.006
5 mg / 200 gm rat
16 mg / 200 gm rat
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
Graded-Dose Response Curve SECTION C Celecoxib
Foot Volume
Prepar ation: 200 mg tablet 0.3 mg / 200 Doses: gm rat
Carageena Before n
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.001 0.002 0.001 0.004 0.001 0.002 0.002 0.002
0 0.005 0.003 0.006 0.004 0.003 0.007
Prednisone 1 hr
0.007 0.006 0.004 0.002 0.003 0.002 0.006
2 hrs 3 hrs
0.002 0.003 0.003 0.006 0.003 0.003 0.003
Before
Caragee nan
1 hr
2 hrs
3 hrs
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.004 0.004 0.002 0.004 0.001 0.001 0.003 0.002
0.001 0.005 0.004 0.005 0.004 0.001 0.003 0.006
0.006 0.005 0.005 0.005 0.006 0.006 0.005 0.002
0.002 0.003 0.004 0.003 0.002 0.003 0.001 0.002
0.005 0.003 0.005 0.002 0.005 0.002 0.003 0.001
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.001 0.004 0.002 0.001 0.002 0.002 0.003
0.004 0.006 0.001 0.005 0.005 0.005 0.002 0.003
0.005 0.005 0.004 0.002 0.005 0.004 0.005 0.005
0.003 0.002 0.004 0.002 0.002 0.006 0.005 0.005
0.007 0.001 0.006 0.001 0.005 0.004 0.003 0.003
0.2 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.003 0.001 0.002 0.002 0.004 0.002 0.001 0.001
0.003 0.004 0.004 0.003 0.006 0.003 0.005 0.003
0.001 0.002 0.006 0.005 0.001 0.005 0.005 0.006
0.005 0.005 0.004 0.004 0.004 0.004 0.004 0.004
0.005 0.002 0.002 0.004 0.004 0.005 0.001 0.003
0.6 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.003 0.001 0.003 0.001 0.003 0.001 0.003 0.004
0.007 0.003 0.003 0.003 0.006 0.005 0.003 0.004
0.002 0.006 0.006 0.003 0.005 0.005 0.005 0.005
0.005 0.005 0.004 0.006 0.006 0.007 0.003 0.001
0.005 0.004 0.002 0.006 0.004 0.006 0.004 0.003
0.06 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
10 mg / 200 gm rat
Foot Volume
Preparat ion: 20 mg tablet 0.02 mg / 200 Doses: gm rat
0.003 0.006 0.002 0.006 0.001 0.004 0.002
1 mg / 200 gm rat
3 mg / 200 gm rat
Graded-Dose Response Curve SECTION D
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.004 0.001 0.006 0.003 0.003 0.005 0.003 0.004
0.003 0.005 0.004 0.005 0.001 0.002 0.006 0.005
0.003 0.004 0.006 0.005 0.005 0.005 0.007 0.006
0.006 0.004 0.004 0.005 0.005 0.006 0.007 0.008
0.007 0.006 0.005 0.007 0.006 0.005 0.007 0.004
0.007 0.005 0.005 0.005 0.004 0.006 0.005 0.006
0.003 0.004 0.002 0.005 0.005 0.004 0.003 0.004
0.004 0.006 0.005 0.003 0.003 0.004 0.008 0.003
0.006 0.006 0.005 0.005 0.006 0.003 0.005 0.002
0.001 0.002 0.005 0.001 0.001 0.005 0.001 0.003
0.003 0.004 0.003 0.002 0.004 0.003 0.004 0.004
0.005 0.004 0.002 0.003 0.003 0.003 0.003 0.002
0.007 0.003 0.001 0.006 0.001 0.005 0.004 0.003
0.003 0.002 0.002 0.001 0.002 0.004 0.003 0.001
0.003 0.002 0.002 0.006 0.004 0.003 0.002 0.006
Outline • • • •
Introduction Objectives Materials and Methods Results Expected Actual
• Discussion • Conclusion
DOSE-EFFECT RELATIONSHIP • The intensity and duration of a drug’s effects are a function of the drug dose and drug concentration at the effect site • X-axis – drug concentration • Y-axis – response
DOSE-RESPONSE CURVE
TYPES OF DOSE-RESPONSE RELATIONSHIPS GRADED DOSE-RESPONSE
QUANTAL DOSE-RESPONSE
• Continuous scale (↑dose → ↑ effect)
• All-or-none pharmacologic effect
• Measured in a single biologic unit
• Population studies
• Relates dose to intensity of effect
• Relates dose to frequency of effect
DOSE-RESPONSE CURVE POTENCY
MAXIMAL EFFICACY
• Relative position of the doseresponse curve along the dose axis
• Determined principally by the properties of the drug and its receptor-effector system • Reflected in the plateau of the dose-response curve • Shows the clinical effectiveness of a drug
OBJECTIVES • GENERAL To compare the anti-inflammatory properties of aspirin, paracetamol, celecoxib, and prednisone using the grade dose-response curve.
• SPECIFIC To determine the percent (%) response to inhibition of inflammation with aspirin, paracetamol, celecoxib and prednisone on Carrageenan-induced foot edema of rats. To compare the relative potency and maximal efficacy of aspirin, paracetamol, celecoxib, and prednisone antiinflammatory using the graded dose-response curve.
MATERIALS AND METHODS • 12 week old rats • Phlogistic Agent (Carrageenan) • Gavage Tubes, Syringe • Mercury Set-up • Drugs ▫ ▫ ▫ ▫
Paracetamol Aspirin Celecoxib Prednisone
Doses : per 200 g rat
Carrageenan • phlogistic agent of choice for testing antiinflammatory agents both steroidal and nonsteroidal • is a mucopolysaccharide derived from Irish sea moss, Chondrus
Katzung. Basic and Clinical Pharmacology, 10th ed.
COX-2 Inhibitors Pathway
CELECOX IB
PARACETAMOL • Weak COX-1 and COX-2 inhibitor due to
activity in the brain • No significant anti-inflammatory effects; more on analgesic effects RECENT STUDIES:
• selective inhibition of the enzyme COX-3 in the brain and spinal cord
ASPIRIN • Anti-platelet (160-325mg/day) ▫ Inhibits synthesis of TXA
• Antipyretic (325-650mg/4 hrs) ▫ Inhibit PGE2
• Anti inflammatory (4-6gday) ▫ COX-1 and COX-2
CELECOXIB • Selective COX-2 inhibitor ▫ Effective anti-inflammatory drug
PREDNISONE • Glucocorticoids • anti-inflammatory and immunosuppressive effect • inhibits Phospholipase A2 • COX-2 inhibiting effects as the NSAIDs
% difference (inflammation) = (reading after - reading before injection of phlogistic agent) reading before injection of phlogistic agent % inhibition = (reading before injection of phlogistic agent - reading after ) reading before injection of phlogistic agent
RESULTS Expected ▫ Anti-inflammatory property (Efficacy) Prednisone > Celecoxib =Aspirin > Paracetamol
▫ Potency Prednisone > Celecoxib > Paracetamol > Asprin
RESULTS Actual ▫ Anti-inflammatory property (Efficacy) Celecoxib =Aspirin > Prednisone> Paracetamol
▫ Potency Prednisone > Celecoxib > Paracetamol = Asprin
SOURCES OF ERROR • • • • •
Variability in handling Initial inflammation Drug was not fully dissolved in NSS Spillage during gavage feeding Measurement of foot volume Mercury level Reader variability
Graded-Dose Response Curve SECTION A Paracetamol
Graded-Dose Response Curve SECTION B
Foot Volume
Preparati on: 500 mg tablet 0.5 mg / 200 Doses: gm rat
Before
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.002 0.003 0.002 0.002 0.002 0.001 0.001
Caragee nan
0.002 0.002 0.001 0.003 0.004 0.003 0.004 0.008
Aspirin 1 hr
0.005 0.006 0.007 0.004 0.005 0.005 0.004 0.005
2 hrs 3 hrs
0.004 0.005 0.006 0.004 0.002 0.004 0.005 0.004
0.004 0.005 0.007 0.005 0.006 0.005 0.007 0.003
1.6 mg / 200 gm rat
Foot Volume
Preparati on: 200 mg tablet 0.5 mg / 200 Doses: gm rat
Before
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.002 0.001 0.003 0.001 0.001 0.002 0.001
Carageen an 1 hr
0.002 0.002 0.003 0.003 0.001 0.001 0.005 0.001
0.002 0.005 0.001 0.002 0.003 0.008 0.002 0.001
2 hrs 3 hrs
0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
0.004 0.003 0.001 0.001 0.002 0.003 0.001 0.001
1.6 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.002 0.002 0.002 0.002 0.001 0.002 0.001
0.003 0.005 0.004 0.004 0.004 0.001 0.003 0.004
0.006 0.005 0.005 0.004 0.005 0.003 0.006 0.007
0.002 0.002 0.005 0.005 0.006 0.005 0.004 0.005
0.007 0.004 0.005 0.004 0.005 0.005 0.003 0.008
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.004 0.003 0.004 0.002 0.003 0.002 0.003 0.003
0.002 0.003 0.004 0.003 0.005 0.005 0.004 0.005
0.004 0.002 0.004 0.001 0.001 0.003 0.003 0.001
0.003 0.002 0.002 0.001 0.002 0.003 0.003 0.003
0.004 0.004 0.002 0.001 0.002 0.001 0.001 0.001
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.001 0.001 0.001 0.001 0.001 0.002 0.001 0.001
0.001 0.003 0.002 0.006 0.004 0.002 0.006 0.002
0.003 0.003 0.005 0.007 0.003 0.001 0.006 0.004
0.004 0.004 0.007 0.004 0.003 0.003 0.005 0.002
0.003 0.006 0.005 0.005 0.005 0.004 0.004 0.006
5 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.003 0.002 0.003 0.002 0.005 0.006 0.004
0.003 0.003 0.003 0.002 0.003 0.003 0.007 0.005
0.002 0.002 0.002 0.002 0.005 0.003 0.005 0.002
0.002 0.001 0.001 0.001 0.005 0.004 0.004 0.003
0.002 0.002 0.001 0.001 0.001 0.002 0.003 0.002
16 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.001 0.002 0.001 0.002 0.001 0.001 0.001 0.001
0.001 0.004 0.002 0.002 0.004 0.003 0.002 0.003
0.004 0.005 0.003 0.005 0.004 0.005 0.007 0.005
0.008 0.004 0.005 0.004 0.005 0.006 0.006 0.004
0.005 0.005 0.007 0.005 0.005 0.003 0.004 0.005
0.003 0.001 0.004 0.002 0.002 0.001 0.001 0.001
0.001 0.002 0.001 0.001 0.002 0.001 0.001 0.001
0.001 0.007 0.001 0.004 0.001 0.001 0.001 0.001
0.001 0.004 0.001 0.001 0.002 0.001 0.002 0.004
0.001 0.001 0.001 0.001 0.001 0.008 0.001 0.006
5 mg / 200 gm rat
16 mg / 200 gm rat
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
Graded-Dose Response Curve SECTION C Celecoxib
Foot Volume
Prepar ation: 200 mg tablet 0.3 mg / 200 Doses: gm rat
Carageena Before n
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.001 0.002 0.001 0.004 0.001 0.002 0.002 0.002
0 0.005 0.003 0.006 0.004 0.003 0.007
Prednisone 1 hr
0.007 0.006 0.004 0.002 0.003 0.002 0.006
2 hrs 3 hrs
0.002 0.003 0.003 0.006 0.003 0.003 0.003
Before
Caragee nan
1 hr
2 hrs
3 hrs
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.004 0.004 0.002 0.004 0.001 0.001 0.003 0.002
0.001 0.005 0.004 0.005 0.004 0.001 0.003 0.006
0.006 0.005 0.005 0.005 0.006 0.006 0.005 0.002
0.002 0.003 0.004 0.003 0.002 0.003 0.001 0.002
0.005 0.003 0.005 0.002 0.005 0.002 0.003 0.001
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.002 0.001 0.004 0.002 0.001 0.002 0.002 0.003
0.004 0.006 0.001 0.005 0.005 0.005 0.002 0.003
0.005 0.005 0.004 0.002 0.005 0.004 0.005 0.005
0.003 0.002 0.004 0.002 0.002 0.006 0.005 0.005
0.007 0.001 0.006 0.001 0.005 0.004 0.003 0.003
0.2 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.003 0.001 0.002 0.002 0.004 0.002 0.001 0.001
0.003 0.004 0.004 0.003 0.006 0.003 0.005 0.003
0.001 0.002 0.006 0.005 0.001 0.005 0.005 0.006
0.005 0.005 0.004 0.004 0.004 0.004 0.004 0.004
0.005 0.002 0.002 0.004 0.004 0.005 0.001 0.003
0.6 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.003 0.001 0.003 0.001 0.003 0.001 0.003 0.004
0.007 0.003 0.003 0.003 0.006 0.005 0.003 0.004
0.002 0.006 0.006 0.003 0.005 0.005 0.005 0.005
0.005 0.005 0.004 0.006 0.006 0.007 0.003 0.001
0.005 0.004 0.002 0.006 0.004 0.006 0.004 0.003
0.06 mg / 200 gm rat Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
10 mg / 200 gm rat
Foot Volume
Preparat ion: 20 mg tablet 0.02 mg / 200 Doses: gm rat
0.003 0.006 0.002 0.006 0.001 0.004 0.002
1 mg / 200 gm rat
3 mg / 200 gm rat
Graded-Dose Response Curve SECTION D
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8
0.004 0.001 0.006 0.003 0.003 0.005 0.003 0.004
0.003 0.005 0.004 0.005 0.001 0.002 0.006 0.005
0.003 0.004 0.006 0.005 0.005 0.005 0.007 0.006
0.006 0.004 0.004 0.005 0.005 0.006 0.007 0.008
0.007 0.006 0.005 0.007 0.006 0.005 0.007 0.004
0.007 0.005 0.005 0.005 0.004 0.006 0.005 0.006
0.003 0.004 0.002 0.005 0.005 0.004 0.003 0.004
0.004 0.006 0.005 0.003 0.003 0.004 0.008 0.003
0.006 0.006 0.005 0.005 0.006 0.003 0.005 0.002
0.001 0.002 0.005 0.001 0.001 0.005 0.001 0.003
0.003 0.004 0.003 0.002 0.004 0.003 0.004 0.004
0.005 0.004 0.002 0.003 0.003 0.003 0.003 0.002
0.007 0.003 0.001 0.006 0.001 0.005 0.004 0.003
0.003 0.002 0.002 0.001 0.002 0.004 0.003 0.001
0.003 0.002 0.002 0.006 0.004 0.003 0.002 0.006
