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Published ahead of print on June 7, 2007, doi:10.1164/rccm.200703-500OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 706-712, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200703-500OC

Original Article

Effects of Continuous Positive Airway Pressure on Early Signs of Atherosclerosis in Obstructive Sleep Apnea

Luciano F. Drager1, Luiz A. Bortolotto1, Adelaide C. Figueiredo2, Eduardo M. Krieger1 and Geraldo Lorenzi-Filho2

1 Hypertension Unit and 2 Sleep Laboratory, Pulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil

Correspondence and requests for reprints should be addressed to Luciano F. Drager, M.D., Hypertension Unit–Heart Institute (InCor), University of São Paulo Medical School, Av Dr Enéas Carvalho de Aguiar, 44, CEP 05403-904 São Paulo, Brazil. E-mail: luciano.drager{at}incor.usp.br


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Obstructive sleep apnea (OSA) is associated with adverse cardiovascular outcomes, including myocardial infarction and stroke. Atherosclerosis is a key mechanism for these cardiovascular events. Recent cross-sectional studies showed the presence of early signs of atherosclerosis in patients with OSA who were free of comorbidities.

Objectives: To determine the impact of treatment with continuous positive airway pressure (CPAP) on atherosclerosis.

Methods: We randomly assigned 24 patients with severe OSA (age, 46 ± 6 yr) who were free of comorbidities to receive no treatment (control, n = 12) or CPAP (n = 12) for 4 months. Carotid intima-media thickness, arterial stiffness (evaluated by pulse-wave velocity), carotid diameter, 24-hour blood pressure monitoring, C-reactive protein, and catecholamines were determined at baseline and after 4 months.

Measurements and Main Results: At baseline, all measurements were similar in both groups and did not change in the control group after 4 months. In contrast, a significant decrease occurred in carotid intima-media thickness (707 ± 105 vs. 645 ± 95 µm, P = 0.04), pulse-wave velocity (10.4 ± 1.0 vs. 9.3 ± 0.9 m/s, P < 0.001), C-reactive protein (3.7 ± 1.8 vs. 2.0 ± 1.2 mg/L, P = 0.001), and catecholamines (365 ± 125 vs. 205 ± 51 ng/ml, P < 0.001) after 4 months of CPAP. Carotid diameter did not change significantly. Regarding the whole group, changes in carotid intima-media thickness were correlated with changes in catecholamines (r = 0.41, P < 0.05). Changes in pulse-wave velocity were correlated with changes in C-reactive protein (r = 0.58, P < 0.01) and catecholamines (r = 0.54, P < 0.01).

Conclusions: The treatment of OSA significantly improves early signs of atherosclerosis, supporting the concept that OSA is an independent risk factor for atherosclerosis.

Clinical trial registered with www.clinicaltrials.gov (NCT 00400543).

Key Words: obstructive sleep apnea • intima-media thickness • arterial stiffness • atherosclerosis • continuous positive airway pressure



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Obstructive sleep apnea (OSA) is associated with increased risk of myocardial infarction and stroke. OSA has been associated with atherosclerosis, a key mechanism for these cardiovascular events.

What This Study Adds to the Field
This randomized study showed that effective treatment of OSA with continuous positive airway pressure for 4 months significantly improves early signs of atherosclerosis in patients with severe OSA. These results suggest that OSA is an independent risk factor for atherosclerosis.

 
Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete obstruction of the upper airway during sleep, resulting in oxygen desaturation and arousals from sleep (1). OSA is recognized as an important public health problem, affecting 9 and 24% of middle-aged females and males, respectively (2). Compelling evidence now indicates that severe OSA is associated with increased cardiovascular morbidity and mortality, mainly due to acute myocardial infarction and stroke (3, 4). One uncontrolled observational study showed that continuous positive airway pressure (CPAP), the standard treatment for OSA, was associated with decreased nonfatal and fatal cardiovascular events (4). However, the mechanisms linking OSA and poor cardiovascular outcome are not completely understood.

Several mechanisms associated with OSA are potentially harmful to the cardiovascular system, including systemic inflammation, sympathetic activation, production of reactive oxygen species, and endothelial dysfunction (5). Together, all these factors could contribute to atherosclerosis progression, a key mechanism implicated in myocardial infarction and stroke (6). OSA could also contribute to atherosclerosis indirectly, by causing systemic hypertension, insulin resistance, and impaired lipid metabolism (5, 7, 8). Recently, Savransky and colleagues demonstrated that chronic intermittent hypoxia, a hallmark of OSA, induces atherosclerosis in mice (9). The studies in humans are difficult because the patients with OSA frequently have numerous risk factors for atherosclerosis. However, the demonstration of early signs of atherosclerosis in patients with OSA who were free of hypertension or other significant comorbidities (10) suggests an independent association between OSA and atherosclerosis.

We performed a randomized study to evaluate the hypothesis that the treatment of OSA with CPAP therapy significantly improves validated markers of early signs of atherosclerosis (11–13), namely carotid intima-media thickness (primary outcome), arterial stiffness, and carotid diameter (secondary outcomes). We also measured 24-hour blood pressure monitoring, plasma C-reactive protein, and catecholamines. To test the hypothesis that OSA contributes to atherosclerosis directly, we only included patients with severe OSA who were free of comorbidities. Some of the results of these studies have been previously reported in the form of an abstract (14).


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The patients were recruited from the Sleep Laboratory, Heart Institute (InCor), University of São Paulo Medical School (Brazil). Over a 2-year period (January 2004 to January 2006), all male adults with a sleep study within 1 month showing severe OSA (>30 events of apnea and hypopnea per hour of sleep) and naive to treatment were considered for the study. To minimize confounding risk factors for atherosclerosis, we excluded subjects older than 60 years and those with a body mass index (BMI) greater than 35 kg/m2, diabetes mellitus, hypertension, cerebrovascular disease, valvular heart disease, renal failure, current or past smoking history, and chronic use of any medication. Hypertension was excluded after three or more normal blood pressure values (<140/90 mm Hg) obtained on separate occasions with a conventional mercury sphygmomanometer (15).

The study was approved by the local institutional review board and all patients gave written, informed consent.

Sleep Study
All patients underwent a standard overnight polysomnography (EMBLA; Flagra hf. Medical Devices, Reykjavik, Iceland), including electroencephalography, electrooculography, electromyography, oximetry, measurements of airflow (oronasal thermistor and pressure cannula), and measurements of rib cage and abdominal movements during breathing, as previously described (10). Apnea was defined as complete cessation of airflow for at least 10 seconds, associated with oxygen desaturation of 3%. Hypopnea was defined as a significant reduction (>50%) in respiratory signals for at least 10 seconds associated with oxygen desaturation of 3%. The apnea–hypopnea index was calculated as the total number of respiratory events (apneas plus hypopneas) per hour of sleep. All patients were naive to treatment. Daytime somnolence was evaluated by the Epworth Sleepiness Scale (16).

The participants were randomly assigned to no treatment (control) or treatment with CPAP (REMStar Pro with C-Flex; Respironics, Inc., Murrysville, PA) for 4 months, according to a computer-generated list of random numbers. The ideal CPAP was determined for all participants by an overnight sleep study titration, during which the pressure was adjusted to abolish apnea and hypopnea. CPAP compliance was objectively measured by downloading a card (Smart Card; Respironics, Inc.) once per week in the first month and twice per month thereafter. After the end of the study, all patients randomized to the control group were treated with CPAP.

Study Procedures
Vascular properties, blood samples, and 24-hour blood pressure monitoring were performed at study entry and after 4 months.

Vascular properties.
All participants had their vascular properties evaluated by an experienced observer (L.A.B.), blinded to the randomization. All measurements were taken between 2:00 and 4:00 P.M., with the patient in a recumbent position while awake. Carotid intima-media thickness was measured with a high-resolution echo-tracking system (Wall Track System; Neurodata, Bilthoven, The Netherlands) coupled with a conventional two-dimensional vascular echograph (Sigma 44 Kontrom; Sigma 44 Kontrom Instruments, Watford, UK) equipped with a 7.5-MHz probe. The vascular measurements were performed on the right common carotid arteries 1 cm below the bifurcation at the site of the distal wall. Intima-media thickness was measured at the thickest point, on the near and far walls with a specially designed computer program. A high rate of intima-media thickness reproduction has been previously demonstrated (17). Plaque was defined as a localized thickening of more than 1.2 mm that did not uniformly involve the whole artery (10). Arterial stiffness was determined by carotid-femoral pulse-wave velocity with a noninvasive automatic device, Complior (Colson, Garges les Gonesses, France). The pulse-wave velocity measurement technique, and its validation and reproducibility, has been described previously (10, 18). Measurements were repeated over 10 different cardiac cycles, and the mean was used for the final analysis. The distance traveled by the pulse wave was measured over the body surface as the distance between the two recording sites (D), whereas pulse transit time (t) was automatically determined by the Complior. Pulse-wave velocity was automatically calculated as D/t (18).

During vascular measurements, a continuous noninvasive blood pressure recording was obtained by using the Portapres device (TNO Biomedical Instrumentation, Amsterdam, The Netherlands), which has been shown to accurately estimate intraarterial blood pressure (19). This method has a height correction unit to compensate finger measurements with the heart level. The means of six stable measurements were used for the final analysis.

Blood samples.
Venous blood was collected from all participants between 8:00 and 10:00 A.M. for the measurement of glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein, and red blood cell count. High-sensitivity C-reactive protein and plasma catecholamine (norepinephrine) were measured by latex particle-enhanced immunoturbidimetric assay and high-performance liquid chromatography, respectively.

24-hour blood pressure monitoring.
All participants underwent 24-hour blood pressure monitoring with a SpaceLabs device (model 90207; SpaceLabs Medical, Inc., Issaquah, WA). Blood pressure was measured every 10 minutes during the day (8:00 A.M. to 11:00 P.M.) and every 20 minutes during the night (11:00 P.M. to 8:00 A.M.) with an appropriate cuff placed on a nondominant arm. Participants were instructed to perform their ordinary daily activities and not to move their arm during the ongoing measurement.

Statistical Analysis
Carotid intima-media thickness was the primary outcome. Secondary outcome variables included pulse-wave velocity, carotid diameter, C-reactive protein, and plasma catecholamine. Data were analyzed with Statistica 5.0 software (Statsoft, Tulsa, OK). Baseline characteristics of patients with OSA according to the group assigned were compared by two-tailed unpaired t tests for continuous variables and Fisher's exact test for nominal variables. Two-way repeated-measures analysis of variance and Tukey's test were used to compare differences within and between groups in variables measured at baseline and 4 months. We performed Pearson correlations between changes in vascular parameter and changes in possible explanatory variables, including BMI, cholesterol, 24-hour blood pressure, C-reactive protein, and catecholamine. In our study, all variables had a normal distribution and are expressed as mean ± SD. A value of P < 0.05 was considered significant.


   RESULTS
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of approximately 400 patients with established severe OSA, we studied 24 patients according to our rigorous exclusion criteria (Figure 1). The majority of the screened patients were not included because of one or more comorbidities, including hypertension, diabetes, smoking habit, and chronic use of medications. The participants were predominantly middle-aged and overweight with severe OSA. There were no losses in the follow-up. Patients assigned to control or CPAP groups were similar (Table 1).


Figure 1
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  		Figure 1. Flow diagram of the progress through the phases of the study. *Some patients had multiple exclusions; {dagger}medications other than for the treatment of conditions above.

 

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  		TABLE 1. BASELINE CHARACTERISTICS OF THE PATIENTS ASSIGNED TO NO TREATMENT (CONTROL) OR CONTINUOUS POSITIVE AIRWAY PRESSURE

 
Effects of CPAP
The apnea–hypopnea index was virtually abolished after CPAP titration (4.5 ± 1.9 events/h). The optimal CPAP was 10.4 ± 1.1 cm H2Or (range, 8.8–12 cm H2O). The CPAP was used for 6 ± 0.6 hours per night (range, 5–6.6 h). After 4 months of randomization, sleepiness (evaluated by Epworth score) did not change in the control group (13 ± 5 to 13 ± 4) and decreased significantly in the CPAP group (14 ± 4 to 7 ± 2, P < 0.001).

No significant changes occurred in BMI, waist-to-hip ratio, heart rate, glucose, and cholesterol levels over the study period in both the control and CPAP groups (Table 2). As expected according to the characteristics of the population included in this study, no carotid plaque was observed in any participant. Carotid intima-media thickness (Figure 2), pulse-wave velocity (Figure 3), carotid diameter (Figure 4), C-reactive protein, and catecholamines (Table 2) were similar across the study period in the control group. In contrast, the group treated with CPAP had a significant decrease in carotid intima-media thickness (Figure 2), pulse-wave velocity (Figure 3), C-reactive protein, and catecholamines (Table 2). Carotid diameter did not decrease significantly in the CPAP group (Figure 4). We also found a small decrease in 24-hour diastolic blood pressure in the group assigned to CPAP, but this decrease was not significant when compared with control subjects (Table 2). In addition, changes in carotid intima-media thickness and pulse-wave velocity did not correlate with changes in 24-hour diastolic blood pressure (P > 0.2). Changes in carotid intima-media thickness were only significantly correlated with changes in catecholamines (r = 0.41, P < 0.05). The changes in pulse-wave velocity were correlated with changes in C-reactive protein (r = 0.58, P < 0.01) and catecholamines (r = 0.54, P < 0.01).


Figure 2
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  		Figure 2. Individual values for the intima-media thickness. In the control group, intima-media thickness from baseline to 4 months (from 732 ± 164 to 740 ± 150 µm; 95% confidence interval [CI], –20.69 to 36.86) was similar. In contrast, intima-media thickness significantly decreased in the group randomized to continuous positive airway pressure (CPAP) therapy (from 707 ± 105 to 645 ± 95 µm; 95% CI, –110.2 to –14.07; P = 0.04). The differences between groups remained significant (P = 0.02). NS denotes not significant. Short horizontal lines and bars are mean ± SD.

 

Figure 3
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  		Figure 3. Individual values for the arterial stiffness, evaluated by carotid–femoral pulse-wave velocity analysis. In the control group, pulse-wave velocity from baseline to 4 months (from 10.1 ± 1.3 to 10.3 ± 1.3 m/s; 95% confidence interval [CI], –0.17 to 0.52) was similar. In contrast, pulse-wave velocity decreased in all 12 subjects treated with continuous positive airway pressure (CPAP), and the mean decrease was significant (from 10.4 ± 1.0 to 9.3 ± 0.9 m/s; 95% CI, –1.47 to –0.73; P < 0.001). The differences between groups were significant (P < 0.001). NS denotes not significant. Short horizontal lines and bars are mean ± SD.

 

Figure 4
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  		Figure 4. Individual values for the carotid diameter in all patients. In both groups, there were no significant changes in carotid diameter from baseline to 4 months (7,279 ± 722 to 7,367 ± 810 µm in controls; 95% confidence interval [CI], –29.66 to 205.33; and 7,095 ± 686 vs. 6,988 ± 461 µm in the continuous positive airway pressure [CPAP] group; 95% CI, –308.81 to 94.48). NS denotes not significant. Short horizontal lines and bars are mean ± SD.

 

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  		TABLE 2. CHARACTERISTICS AT BASELINE AND AFTER 4 MONTHS OF RANDOMIZATION IN OBSTRUCTIVE SLEEP APNEA GROUPS

 

   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our results demonstrate that 4 months of effective treatment with CPAP significantly improves validated markers of atherosclerosis in normotensive middle-aged men with severe OSA. In addition, improvements in these early vascular markers were associated with reductions in markers of inflammation and sympathetic activation, as evaluated by plasma C-reactive protein and catecholamine, respectively. These effects were noted without changes in weight or lipids. Taken together, the results from the present study provide evidence that OSA is an independent risk factor for atherosclerosis.

OSA is independently associated with increased risk of fatal cardiovascular events that can be reversed by treatment with CPAP (4). However, the mechanisms are not completely understood. Atherosclerosis is a unifying mechanism that may help to explain the increased risk for myocardial infarction and stroke associated with OSA (3, 4). The demonstration of an independent association between OSA and atherosclerosis is difficult because the majority of the patients with OSA share several risk factors for atherosclerosis, including hypertension, diabetes, and obesity (5). Recently, a cross-sectional study described early signs of atherosclerosis in patients with OSA who were free of significant comorbidities (10). The present randomized study now adds to the current knowledge by showing that CPAP can reverse validated markers of atherosclerosis (11–13) in patients with the similar characteristics. This unique study design allowed the isolation of OSA as an independent risk factor for atherosclerosis. Interestingly, patients assigned to CPAP therapy reverted intima-media thickness and pulse-wave velocity to values that are in the same range as that previously reported in appropriate control subjects with no OSA (10) (645 ± 95 vs. 604 ± 83 µm for intima-media thickness and 9.3 ± 0.9 vs. 8.7 ± 0.8 m/s for pulse-wave velocity, respectively). The clinical importance of such findings is based on evidence that early detection of atherosclerotic disease processes and subsequent therapeutic interventions can significantly alter the natural course of cardiovascular disease (20, 21).

There are several pathways by which OSA may contribute to atherosclerosis progression, including endothelial dysfunction, systemic inflammation, oxidative stress, vascular smooth cell activation, increased adhesion molecule expression, lymphocyte activation, increased lipid lowering in macrophages, lipid peroxidation, and high-density lipoprotein dysfunction (5, 22–28). Recent evidence suggests that snoring is related to energy transmission to the carotid artery, which could also be involved in atherosclerosis progression (29). Interestingly, CPAP treatment could reverse several of these pathways (5), and there is evidence that CPAP withdrawal reestablishes important mechanisms involved in atherosclerosis progression, such as endothelial dysfunction (30). The present study was not specifically designed to evaluate the effects of CPAP on all of these mechanisms. It is well established that inflammation plays a central role in the development, progression, and outcomes of atherosclerosis (31). C-reactive protein is an important serum marker of systemic inflammation and is associated with pulse-wave velocity in apparently healthy individuals (32). In addition, increased sympathetic activity may also play a role in vascular remodeling. There is evidence that femoral artery wall thickness is associated with the level of sympathetic nerve activity in healthy men (33). Patients with OSA have increased levels of C-reactive protein and catecholamines (5). It has been demonstrated that these markers decrease after treatment with CPAP (34–36). Therefore, the observation of a decrease of C-reactive protein and catecholamine in our patients treated with CPAP is consistent with previous studies (34–36). The correlation between decrease in carotid intima-media thickness and decrease in catecholamines as well as between decrease in pulse-wave velocity and decrease in C-reactive protein and catecholamines observed in our study points to plausible mechanisms to explain the vascular improvement associated with OSA treatment.

The observation of a small, but significant decrease in diastolic blood pressure in normotensive patients after treatment with CPAP in our study is consistent with a previous report (37). The changes in blood pressure in the CPAP group were not significantly different from the control group (P = nonsignificant for the comparisons between the groups; Table 2). It is important to consider that the lack of significance can probably be attributed to a lack of power to detect significant drops in arterial blood pressure in subjects without hypertension, rather than to a lack of effect. The reduction on blood pressure could be an indirect mechanism by which CPAP improved vascular markers of atherosclerosis. However, changes in blood pressure were small and did not correlate with changes in vascular parameters, and therefore are unlikely to explain our results. On the other hand, repetitive surges in blood pressure during each respiratory event may play an important role in vascular damage even in normotensive patients (38). These blood pressure oscillations occur in concert with respiratory events (in our study, ~60 events/h of sleep) and may not be detected by 24-hour blood pressure monitoring (three blood pressure measurements per hour during the night).

Dyslipidemia is another important factor associated with atherosclerosis progression (6, 31). Our selected group of patients had mild dyslipidemia. Even in our select group, patients and control subjects presented high borderline levels of low-density lipoprotein. However, patients randomized to both control and CPAP had similar levels of total cholesterol, low-density lipoprotein, and high-density lipoprotein at baseline and after 4 months (Table 2).

The biological relevance of our data can be evidenced when we compare the impact of CPAP on vascular parameters with traditional forms of treatments for important risk factors to acute myocardial infraction and stroke, such as hypertension and dyslipidemia. Long-term studies showed that statins reduced intima-media thickness after 6 months of therapy (39). Therefore, the observation of a significant reduction (9%) on carotid intima-media thickness after only 4 months of effective CPAP is remarkable. In the PLAC II (Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries II) study, carotid intima-media thickness was reduced by 12% after 1 year of treatment with pravastatin therapy as compared with placebo (40). Similarly, the magnitude of improvement in pulse-wave velocity after CPAP observed in our study (10.4%) is in the same range as that observed after 3 months of statin use (11.5%) (41). The Complior study (42) showed a similar reduction in the absolute value of pulse-wave velocity observed in our study (–1.1 ± 1.4 vs. –1.1 ± 0.6 m/s, respectively) after 6 months of effective antihypertensive treatment of patients with hypertension. Interestingly, CPAP may share some similarities with the independent lipid-lowering effects (referred to as pleiotropic) of statins, including reduction in inflammation (41, 43, 44).

Our study has some limitations. First, patients were aware of their treatment assignments and a placebo group using CPAP with ineffective pressure to open the airway was not included. On the other hand, the key measurements of vascular outcome were obtained by one researcher blinded to treatment assignment. Furthermore, the control group had no significant changes in cardiovascular outcomes, results confirmed by the stability of the measurements over the 4-month study period. Therefore, the changes detected in the treatment group can be attributed to CPAP. Second, we only included men with severe OSA who were free of significant comorbidities. Our results may not be extrapolated to women, patients with mild and moderate OSA, and patients with comorbidities. A recent study reported that OSA associated with hypertension had additive effects on arterial stiffness (45). Likewise, the effect of treatment on vascular parameters in typical patients with OSA who have several factors contributing to atherosclerosis is unknown. Patients with OSA with comorbidities have longer standing insults to the vasculature, and may be more resistant to the effects of CPAP. Treatment of OSA is associated with amelioration of several of the companion diseases that are harmful to the cardiovascular system, such as hypertension and insulin resistance (46, 47). In this context, it would be difficult to determine the direct effect of OSA treatment on atherosclerosis. The merit of the present study was the careful selection of patients who were free of overt comorbidities. Finally, evidence suggests that vascular diameter only changes significantly after 1 year of statin therapy (48). Therefore, the absence of a significant reduction in carotid diameter in our study could be explained by the short study period (4 mo). However, a long-term randomized trial in patients with severe OSA would be difficult to perform because of ethical issues involving this severe and symptomatic OSA population.

In conclusion, CPAP therapy improves validated markers of atherosclerosis in patients with OSA, suggesting a direct causal relationship between OSA and atherosclerosis. The effects of CPAP therapy on the early signs of atherosclerosis are multifactorial and are associated with improvements in inflammation and sympathetic activity. Therefore, our results are consistent with and provide mechanistic evidence for the decreased cardiovascular morbidity and mortality associated with OSA (3, 4).


   Acknowledgments
 
The authors are indebted to the Methods in Epidemiologic, Clinical and Operations Research course (MECOR), promoted by the American Thoracic Society, and especially to Gordon D. Rubenfeld, M.D., M.Sc., for his suggestions and critical review of the manuscript.


   FOOTNOTES
 
Supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and the E.J. Zerbini Foundation. All the CPAP machines were provided by Respironics, Inc.

Originally Published in Press as DOI: 10.1164/rccm.200703-500OC on June 7, 2007

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form March 28, 2007; accepted in final form June 7, 2007


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 DISCUSSION
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