Women’s Health
Comparing Pyridoxine and Doxylamine Succinate-Pyridoxine HCl for Nausea and Vomiting of Pregnancy: A Matched, Controlled Cohort Study
The Journal of Clinical Pharmacology 2015, 55(7) 809–814 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.480
Eliza Pope1,2, Caroline Maltepe, Msc1, and Gideon Koren, MD1,3
Abstract Nausea and vomiting of pregnancy (NVP) is a common gestational condition. This is the first study to compare the use of vitamin B6 (pyridoxine) versus Diclectin (doxylamine succinate–pyridoxine HCl) for NVP symptoms. Participants were pregnant women with NVP who used either pyridoxine or doxylamine succinate–pyridoxine HCl for 4 days prior to calling the Motherisk NVP Helpline. Women receiving pyridoxine only (n ¼ 80) were matched to a woman taking doxylamine succinate–pyridoxine HCl only (n ¼ 80), accounting for potential confounders and baseline level of NVP, measured by the Pregnancy Unique Quantification of Emesis (PUQE) score. Change in NVP severity after a week of therapy with either pyridoxine or doxylamine succinate–pyridoxine HCl was quantified using the PUQE-24 scale, which describes NVP symptoms 24 hours prior to their call. Doxylamine succinate–pyridoxine HCl use found a significant reduction in PUQE score, compared with pyridoxine (þ0.5 versus -0.2, P < .05; negative denotes worsening). This association was especially prominent in women with more severe symptoms, where doxylamine succinate–pyridoxine HCl use saw a mean improvement of 2.6 versus 0.4 with pyridoxine (P < .05). As well, doxylamine succinate–pyridoxine HCl use was associated with fewer women experiencing moderate to severe scores after a week of treatment, compared with the pyridoxine group (7 versus 17, P < .05), despite similar baseline PUQE scores.
Keywords nausea, vomiting, pregnancy, pyridoxine, Diclectin
Nausea and vomiting of pregnancy (NVP) is one of the most common conditions during gestation, affecting up to 85% of pregnant women.1 This condition is not only physically debilitating, but also often conveys both an emotional and economic burden on women who suffer from it. Symptoms such as nausea, vomiting, gagging, retching, and dry heaving can range from mild to severe, with the most severe form being hyperemesis gravidarum (HG).2 HG affects up to 3% of pregnant women, and is characterized by severe and persistent nausea and vomiting, weight loss greater than 5% of pre pregnancy weight, dehydration, and nutritional deficiencies, typically requiring hospitalization.3 NVP symptoms usually start between 4 and 9 weeks of pregnancy and peak between 7 and 12 weeks.2,4 In the majority of pregnant women, symptoms cease between 12 and 16 weeks, although some women have symptoms up to 20 weeks’ gestation.2,4 Fewer than 10% of women experience symptoms throughout their entire pregnancy.2,4 The causes of NVP remain unknown and are likely multifactorial; hence, treatment is focused on symptom management.5 Lifestyle and dietary interventions can prove helpful, but the majority of those afflicted require either medicinal or nonmedicinal treatments for their NVP symptoms. The management of NVP is a challenge
for both health care providers and patients, as they often fear the use of pharmacological therapies during pregnancy because of concerns about potential risks to the fetus. The Motherisk Program at the Hospital for Sick Children offers an NVP Helpline for planning-to-bepregnant women and pregnant women and health care
1 Motherisk Program, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada 2 Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada 3 University of Toronto, Toronto, Ontario, Canada
Submitted for publication 1 December 2014; Revised 8 January 2015; accepted 4 February 2015. Corresponding Author: Gideon Koren, MD, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G1X8, Canada Email: [email protected] This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The Motherisk Helpline is supported by Duchesnay Inc. Blainville, Quebec, Canada. G.K. has been a paid consultant for Duchesnay Inc.
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Methods
evidence-based counseling on safe and effective use of medicinal and nonmedicinal management of NVP symptoms.11 Counselors collect information on maternal demographics, medical and obstetrical histories, severity and assessment of NVP symptoms, vitamin use, all medications, and current treatments for NVP for initial calls, as well as at every follow-up call. Cases are prospectively followed up based on Motherisk algorithms that are updated as new evidence becomes available. Cases were collected from records of women who called the Motherisk NVP Helpline for counseling of their NVP symptoms between 2000 and 2014. The use of our NVP surveillance registry has been approved by our hospital’s Research Ethics Board. The study included pregnant women suffering from NVP who called into the Motherisk Helpline. Inclusion criteria included women who at the time of their first call, were taking either pyridoxine or doxylamine succinate–pyridoxine HCl as an antiemetic treatment and had started the treatment at least 3-4 days prior to the call. Women who also used nonmedicinal cointerventions were included. The exclusion criteria were women who were planning their pregnancy, had no NVP symptoms at first call, were taking other antihistamines concomitantly, or were missing information regarding baseline Pregnancy Unique Quantification of Emesis (PUQE) score, PUQE24, or duration of their respective treatments. Demographic, medical, and obstetrical information was collected for the cases that met the inclusion criteria (Table 1). Of 3133 cases of women reporting pyridoxine use, 99 met our inclusion criteria. The 99 eligible pyridoxine cases were then matched to doxylamine succinate–pyridoxine HCl cases based on the following criteria: maternal age ( 3 years), parity ( 1), gestational age (GA) at call ( 1 week), GA at start of NVP symptoms ( 1 week), GA at start of pyridoxine or doxylamine succinate–pyridoxine HCl treatment ( 1 week), vitamin use, and baseline PUQE score ( 1). Cases were excluded if an appropriate match could not be found. This process resulted in a final sample size of 80 cases per arm (Figure 1). The primary end point of comparison was the change in PUQE score over 1 week of therapy with either pyridoxine or doxylamine succinate–pyridoxine HCl using the formula: Difference in PUQE score ¼ PUQE score before therapyPUQE-24 score after therapy with either pyridoxine or doxylamine succinate–pyridoxine HCl.
The study protocol was approved by the Research Ethics Board of the Hospital for Sick Children. As a retrospective analysis, informed consent was not required. This study was conducted at the Motherisk program in Toronto, which established an NVP Helpline in 1996, the first of its kind worldwide. This service offers counseling on food and lifestyle recommendations, in addition to providing
The PUQE -24 is a validated scale for the measurement of severity of NVP symptoms (Figure 2).12–14 The scale ranges from 3 to 15 and is scored on the basis of the sum of individual scores for hours of nausea, number of times vomiting, and number of times retching or dry heaving in the past 24 hours.12
providers requiring evidence-based counseling for the management of NVP symptoms. In Canada and the United States, the delayed-release formulation of 10 mg doxylamine succinate (H1-blocker antihistamine) and 10 mg vitamin B6 (pyridoxine), Diclectin/Diclegis, is currently the only drug labeled by the respective regulatory agencies for treatment for NVP symptoms.6 Diclectin (doxylamine succinate–pyridoxine HCl) has been shown to significantly improve NVP symptoms compared with placebo and has not been associated with an increased risk of adverse pregnancy outcomes.6 This drug is the proposed first-line antiemetic for treatment of NVP symptoms, with a recommended dose of 4 tablets/ day.6 Although doxylamine succinate–pyridoxine HCl is approved in Canada and the United States for NVP, some women prefer nonmedicinal therapies. One such treatment is pyridoxine, or vitamin B6. This water-soluble vitamin was found to be superior to placebo in reducing NVP symptoms, with no adverse fetal effects up to 200 mg/day.7–9 The current recommendation by the Motherisk NVP Helpline, together with the Society of Obstetricians and Gynaecologists of Canada, the American College of Obstetricians and Gynecologists, and the Association of Professors of Obstetrics and Gynecology therefore suggest a maximal daily dose of up to 200 mg/ day.7 However, the relative effectiveness of pyridoxine, compared with its combination with doxylamine, has been only sparsely studied. To date, only the original double-blind, randomized, controlled trial conducted in 1972 compared the efficacy of the constituents of Bendectin, at that time a combination of 10 mg each of doxylamine, pyridoxine, and dicyclomine. The study concluded that dicyclomine did not confer additional therapeutic effect, and it has since been removed from the formulation. In contrast, the study found significant improvements in nausea and vomiting when doxylamine was added to pyridoxine.10 Although the study provided evidence that doxylamine succinate–pyridoxine HCl is more effective than pyridoxine alone, such a comparison has not been replicated since, especially using the formulations available today. The objective of the present study was to conduct a prospective, controlled cohort study to compare the effectiveness of pyridoxine versus doxylamine succinate– pyridoxine HCl in improving NVP symptoms.
Pope et al
811
Table 1. Demographic Information for Both Pyridoxine and Doxylamine Succinate–Pyridoxine HCl Arms
Ethnicity
Education
Marital status
Pyridoxine (n ¼ 80)
Doxylamine Succinate–Pyridoxine HCl (n ¼ 80)
1 (1.3%) 1 (1.3%) 1 (1.3%) 2 (2.5%) 58 (72.5%) 17 (21.3%) 3 (3.8%) 13 (16.3%) 28 (35%) 16 (20%) 20 (25%) 7 (8.8%) 62 (77.5%) 0 (0%) 11 (13.8%)
1 (1.3%) 0 (0%) 1 (1.3%) 4 (5%) 59 (73.8) 12 (15%) 7 (8.8%) 21 (26.3%) 28 (35%) 10 (12.5%) 14 (17.5%) 4 (5%) 65 (81.3%) 3 (3.8%) 8 (10%)
Black or African American Hispanic or Latin American Asian South Asian White Undisclosed High school College University Postgraduate degree Undisclosed Living with partner Married Single Undisclosed
The baseline PUQE score was developed based on a portion of the NVP Helpline initial intake questionnaire that collected data on NVP symptoms a week prior to the first call, including in the last 24 hours (Figure 3). Nausea over the week prior was placed into one of the following categories: always, most time, sometime, rarely/never. Both retching and vomiting were marked as one of the following categories: >5/day, 2–5/day, once/day, 10), mean PUQE improvement was 0.4 with pyridoxine (median, 0) and 2.6 with doxylamine succinate–pyridoxine HCl (median, 2.8; P ¼.02). Despite starting therapy with similar PUQE scores, at the end of 1 week, 17 women receiving pyridoxine had
PUQE scores 10, compared with only 7 in the doxylamine succinate–pyridoxine HCl group (P ¼.03; Table 3).
Discussion This study found that doxylamine succinate–pyridoxine HCl is associated with better symptom control, compared with pyridoxine alone. Women on doxylamine succinate– pyridoxine HCl had significant improvement (þ0.5) in PUQE scores across all severity levels (mild, moderate, severe), whereas pyridoxine was associated with worsening of scores (-0.2). Discrepancy between the 2 groups became even more pronounced in the high- moderate and severe cases, which are classified as cases with a baseline PUQE score >10. In this category, pyridoxine use was
Figure 3. NVP Helpline Questionnaire regarding NVP symptoms in the week prior, with corresponding PUQE scale values.
Pope et al
813
Table 2. Demographics and NVP Characteristics of Pyridoxine and Doxylamine Succinate–Pyridoxine HCl Groups Pyridoxine (n ¼ 80) Maternal age (years), mean (SD)* GA weeks at call (weeks), mean (SD)* Weight at call (pounds), mean (SD) Parity, mean (SD)* Baseline PUQE score, mean (SD)* NVP start week (weeks), mean (SD)* Well-being, mean (SD) Drug daily dose (mg), mean (SD) Drug start (weeks), mean (SD)* Vitamin use, n (%)* Alcohol, n (%) Tobacco, n (%) Street drugs, n (%) Hospital visit, n (%)
32.3 7.9 144.6 0.9 8.0 5.5 4.5 99.1 6.0 78 6 2 1 0
Doxylamine Succinate–Pyridoxine HCl (n ¼ 80)
P Value
32.7 8.1 (1.9) 155.5 (38.4) 0.9 (0.7) 8.0 (2.0) 5.3 (0.9) 4.7 (1.9) 37.9 (11.0)þ 6.5 (1.8) 79 (98.8%) 5 (6.2%) 2 (2.5%) 0 (0%) 3 (3.8%)
.6 .5 .5 .6 1.0 .4 .6
Comparing Pyridoxine and Doxylamine Succinate-Pyridoxine HCl for Nausea and Vomiting of Pregnancy: A Matched, Controlled Cohort Study
The Journal of Clinical Pharmacology 2015, 55(7) 809–814 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.480
Eliza Pope1,2, Caroline Maltepe, Msc1, and Gideon Koren, MD1,3
Abstract Nausea and vomiting of pregnancy (NVP) is a common gestational condition. This is the first study to compare the use of vitamin B6 (pyridoxine) versus Diclectin (doxylamine succinate–pyridoxine HCl) for NVP symptoms. Participants were pregnant women with NVP who used either pyridoxine or doxylamine succinate–pyridoxine HCl for 4 days prior to calling the Motherisk NVP Helpline. Women receiving pyridoxine only (n ¼ 80) were matched to a woman taking doxylamine succinate–pyridoxine HCl only (n ¼ 80), accounting for potential confounders and baseline level of NVP, measured by the Pregnancy Unique Quantification of Emesis (PUQE) score. Change in NVP severity after a week of therapy with either pyridoxine or doxylamine succinate–pyridoxine HCl was quantified using the PUQE-24 scale, which describes NVP symptoms 24 hours prior to their call. Doxylamine succinate–pyridoxine HCl use found a significant reduction in PUQE score, compared with pyridoxine (þ0.5 versus -0.2, P < .05; negative denotes worsening). This association was especially prominent in women with more severe symptoms, where doxylamine succinate–pyridoxine HCl use saw a mean improvement of 2.6 versus 0.4 with pyridoxine (P < .05). As well, doxylamine succinate–pyridoxine HCl use was associated with fewer women experiencing moderate to severe scores after a week of treatment, compared with the pyridoxine group (7 versus 17, P < .05), despite similar baseline PUQE scores.
Keywords nausea, vomiting, pregnancy, pyridoxine, Diclectin
Nausea and vomiting of pregnancy (NVP) is one of the most common conditions during gestation, affecting up to 85% of pregnant women.1 This condition is not only physically debilitating, but also often conveys both an emotional and economic burden on women who suffer from it. Symptoms such as nausea, vomiting, gagging, retching, and dry heaving can range from mild to severe, with the most severe form being hyperemesis gravidarum (HG).2 HG affects up to 3% of pregnant women, and is characterized by severe and persistent nausea and vomiting, weight loss greater than 5% of pre pregnancy weight, dehydration, and nutritional deficiencies, typically requiring hospitalization.3 NVP symptoms usually start between 4 and 9 weeks of pregnancy and peak between 7 and 12 weeks.2,4 In the majority of pregnant women, symptoms cease between 12 and 16 weeks, although some women have symptoms up to 20 weeks’ gestation.2,4 Fewer than 10% of women experience symptoms throughout their entire pregnancy.2,4 The causes of NVP remain unknown and are likely multifactorial; hence, treatment is focused on symptom management.5 Lifestyle and dietary interventions can prove helpful, but the majority of those afflicted require either medicinal or nonmedicinal treatments for their NVP symptoms. The management of NVP is a challenge
for both health care providers and patients, as they often fear the use of pharmacological therapies during pregnancy because of concerns about potential risks to the fetus. The Motherisk Program at the Hospital for Sick Children offers an NVP Helpline for planning-to-bepregnant women and pregnant women and health care
1 Motherisk Program, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada 2 Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada 3 University of Toronto, Toronto, Ontario, Canada
Submitted for publication 1 December 2014; Revised 8 January 2015; accepted 4 February 2015. Corresponding Author: Gideon Koren, MD, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G1X8, Canada Email: [email protected] This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The Motherisk Helpline is supported by Duchesnay Inc. Blainville, Quebec, Canada. G.K. has been a paid consultant for Duchesnay Inc.
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Methods
evidence-based counseling on safe and effective use of medicinal and nonmedicinal management of NVP symptoms.11 Counselors collect information on maternal demographics, medical and obstetrical histories, severity and assessment of NVP symptoms, vitamin use, all medications, and current treatments for NVP for initial calls, as well as at every follow-up call. Cases are prospectively followed up based on Motherisk algorithms that are updated as new evidence becomes available. Cases were collected from records of women who called the Motherisk NVP Helpline for counseling of their NVP symptoms between 2000 and 2014. The use of our NVP surveillance registry has been approved by our hospital’s Research Ethics Board. The study included pregnant women suffering from NVP who called into the Motherisk Helpline. Inclusion criteria included women who at the time of their first call, were taking either pyridoxine or doxylamine succinate–pyridoxine HCl as an antiemetic treatment and had started the treatment at least 3-4 days prior to the call. Women who also used nonmedicinal cointerventions were included. The exclusion criteria were women who were planning their pregnancy, had no NVP symptoms at first call, were taking other antihistamines concomitantly, or were missing information regarding baseline Pregnancy Unique Quantification of Emesis (PUQE) score, PUQE24, or duration of their respective treatments. Demographic, medical, and obstetrical information was collected for the cases that met the inclusion criteria (Table 1). Of 3133 cases of women reporting pyridoxine use, 99 met our inclusion criteria. The 99 eligible pyridoxine cases were then matched to doxylamine succinate–pyridoxine HCl cases based on the following criteria: maternal age ( 3 years), parity ( 1), gestational age (GA) at call ( 1 week), GA at start of NVP symptoms ( 1 week), GA at start of pyridoxine or doxylamine succinate–pyridoxine HCl treatment ( 1 week), vitamin use, and baseline PUQE score ( 1). Cases were excluded if an appropriate match could not be found. This process resulted in a final sample size of 80 cases per arm (Figure 1). The primary end point of comparison was the change in PUQE score over 1 week of therapy with either pyridoxine or doxylamine succinate–pyridoxine HCl using the formula: Difference in PUQE score ¼ PUQE score before therapyPUQE-24 score after therapy with either pyridoxine or doxylamine succinate–pyridoxine HCl.
The study protocol was approved by the Research Ethics Board of the Hospital for Sick Children. As a retrospective analysis, informed consent was not required. This study was conducted at the Motherisk program in Toronto, which established an NVP Helpline in 1996, the first of its kind worldwide. This service offers counseling on food and lifestyle recommendations, in addition to providing
The PUQE -24 is a validated scale for the measurement of severity of NVP symptoms (Figure 2).12–14 The scale ranges from 3 to 15 and is scored on the basis of the sum of individual scores for hours of nausea, number of times vomiting, and number of times retching or dry heaving in the past 24 hours.12
providers requiring evidence-based counseling for the management of NVP symptoms. In Canada and the United States, the delayed-release formulation of 10 mg doxylamine succinate (H1-blocker antihistamine) and 10 mg vitamin B6 (pyridoxine), Diclectin/Diclegis, is currently the only drug labeled by the respective regulatory agencies for treatment for NVP symptoms.6 Diclectin (doxylamine succinate–pyridoxine HCl) has been shown to significantly improve NVP symptoms compared with placebo and has not been associated with an increased risk of adverse pregnancy outcomes.6 This drug is the proposed first-line antiemetic for treatment of NVP symptoms, with a recommended dose of 4 tablets/ day.6 Although doxylamine succinate–pyridoxine HCl is approved in Canada and the United States for NVP, some women prefer nonmedicinal therapies. One such treatment is pyridoxine, or vitamin B6. This water-soluble vitamin was found to be superior to placebo in reducing NVP symptoms, with no adverse fetal effects up to 200 mg/day.7–9 The current recommendation by the Motherisk NVP Helpline, together with the Society of Obstetricians and Gynaecologists of Canada, the American College of Obstetricians and Gynecologists, and the Association of Professors of Obstetrics and Gynecology therefore suggest a maximal daily dose of up to 200 mg/ day.7 However, the relative effectiveness of pyridoxine, compared with its combination with doxylamine, has been only sparsely studied. To date, only the original double-blind, randomized, controlled trial conducted in 1972 compared the efficacy of the constituents of Bendectin, at that time a combination of 10 mg each of doxylamine, pyridoxine, and dicyclomine. The study concluded that dicyclomine did not confer additional therapeutic effect, and it has since been removed from the formulation. In contrast, the study found significant improvements in nausea and vomiting when doxylamine was added to pyridoxine.10 Although the study provided evidence that doxylamine succinate–pyridoxine HCl is more effective than pyridoxine alone, such a comparison has not been replicated since, especially using the formulations available today. The objective of the present study was to conduct a prospective, controlled cohort study to compare the effectiveness of pyridoxine versus doxylamine succinate– pyridoxine HCl in improving NVP symptoms.
Pope et al
811
Table 1. Demographic Information for Both Pyridoxine and Doxylamine Succinate–Pyridoxine HCl Arms
Ethnicity
Education
Marital status
Pyridoxine (n ¼ 80)
Doxylamine Succinate–Pyridoxine HCl (n ¼ 80)
1 (1.3%) 1 (1.3%) 1 (1.3%) 2 (2.5%) 58 (72.5%) 17 (21.3%) 3 (3.8%) 13 (16.3%) 28 (35%) 16 (20%) 20 (25%) 7 (8.8%) 62 (77.5%) 0 (0%) 11 (13.8%)
1 (1.3%) 0 (0%) 1 (1.3%) 4 (5%) 59 (73.8) 12 (15%) 7 (8.8%) 21 (26.3%) 28 (35%) 10 (12.5%) 14 (17.5%) 4 (5%) 65 (81.3%) 3 (3.8%) 8 (10%)
Black or African American Hispanic or Latin American Asian South Asian White Undisclosed High school College University Postgraduate degree Undisclosed Living with partner Married Single Undisclosed
The baseline PUQE score was developed based on a portion of the NVP Helpline initial intake questionnaire that collected data on NVP symptoms a week prior to the first call, including in the last 24 hours (Figure 3). Nausea over the week prior was placed into one of the following categories: always, most time, sometime, rarely/never. Both retching and vomiting were marked as one of the following categories: >5/day, 2–5/day, once/day, 10), mean PUQE improvement was 0.4 with pyridoxine (median, 0) and 2.6 with doxylamine succinate–pyridoxine HCl (median, 2.8; P ¼.02). Despite starting therapy with similar PUQE scores, at the end of 1 week, 17 women receiving pyridoxine had
PUQE scores 10, compared with only 7 in the doxylamine succinate–pyridoxine HCl group (P ¼.03; Table 3).
Discussion This study found that doxylamine succinate–pyridoxine HCl is associated with better symptom control, compared with pyridoxine alone. Women on doxylamine succinate– pyridoxine HCl had significant improvement (þ0.5) in PUQE scores across all severity levels (mild, moderate, severe), whereas pyridoxine was associated with worsening of scores (-0.2). Discrepancy between the 2 groups became even more pronounced in the high- moderate and severe cases, which are classified as cases with a baseline PUQE score >10. In this category, pyridoxine use was
Figure 3. NVP Helpline Questionnaire regarding NVP symptoms in the week prior, with corresponding PUQE scale values.
Pope et al
813
Table 2. Demographics and NVP Characteristics of Pyridoxine and Doxylamine Succinate–Pyridoxine HCl Groups Pyridoxine (n ¼ 80) Maternal age (years), mean (SD)* GA weeks at call (weeks), mean (SD)* Weight at call (pounds), mean (SD) Parity, mean (SD)* Baseline PUQE score, mean (SD)* NVP start week (weeks), mean (SD)* Well-being, mean (SD) Drug daily dose (mg), mean (SD) Drug start (weeks), mean (SD)* Vitamin use, n (%)* Alcohol, n (%) Tobacco, n (%) Street drugs, n (%) Hospital visit, n (%)
32.3 7.9 144.6 0.9 8.0 5.5 4.5 99.1 6.0 78 6 2 1 0
Doxylamine Succinate–Pyridoxine HCl (n ¼ 80)
P Value
32.7 8.1 (1.9) 155.5 (38.4) 0.9 (0.7) 8.0 (2.0) 5.3 (0.9) 4.7 (1.9) 37.9 (11.0)þ 6.5 (1.8) 79 (98.8%) 5 (6.2%) 2 (2.5%) 0 (0%) 3 (3.8%)
.6 .5 .5 .6 1.0 .4 .6
