Pexelizumab and Infarct Size in Patients With Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary InterventionA Delayed Enhancement Cardiac Magnetic Resonance Substudy From the APEX-AMI Trial
Manesh R. Patel, MD*,*,
Stephen G. Worthley, MD, PhD ,
Amanda Stebbins, MS*,
Thorsten Dill, MD ,
Frank E. Rademakers, MD, PhD ,
Uma S. Velleti, MD¶,
Gregory W. Barsness, MD¶,
Frans Van de Werf, MD, PhD,
Christian W. Hamm, MD,
Paul W. Armstrong, MD||,
Christopher B. Granger, MD*,
Raymond J. Kim, MD*
* Duke University, Durham, North Carolina
University of Adelaide, Adelaide, Australia
Kerckhoff-Klinik, Bad Nauheim, Germany
University of Leuven, Leuven, Belgium
¶ Mayo Clinic, Rochester, Minnesota
|| University of Alberta, Edmonton, Alberta, Canada
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Abstract
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Objectives: The purpose of the study was to understand determinants of infarct size in a primary percutaneous intervention (PCI) population treated with pexelizumab compared with placebo.
Background: In the multicenter APEX-AMI (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction) trial, pexelizumab did not reduce 90-day mortality. Cardiac magnetic resonance (CMR) with delayed enhancement was used in a substudy evaluating infarct size and left ventricular ejection fraction (LVEF).
Methods: Consecutive patients undergoing primary PCI for first myocardial infarction (MI) as part of the APEX-AMI trial were enrolled in this substudy at 5 centers. The CMR was completed on days 3 to 5 (n = 99) and day 90 (n = 83) following PCI. Central core lab-masked analyses for quantified LVEF, volumes, and infarct size by planimetry were performed.
Results: Patients were 60 ± 12 years of age, male (n = 83 [84%]), had similar time from symptom onset to presentation (median 2.6 h vs. 2.5 h; p = 1.0), and similar baseline ST-segment deviation (13.5 mm vs. 14 mm; p = 0.59) in both groups. Pexelizumab-treated patients had smaller infarct size (day 3 LV 10.5% vs. 16.2%, p = 0.022; day 90 LV 5.9% vs. 12.4%, p = 0.015) and higher LVEF (day 3 50.3% vs. 46.2%, p = 0.073; day 90 53.9% vs. 49.3%, p = 0.036) compared with placebo-treated patients. The median peak creatine kinase in the pexelizumab group was also significantly less than placebo (922 mg/dl vs. 1,973 mg/dl; p = 0.03). Notably, the pexelizumab group had lower Thrombolysis In Myocardial Infarction (TIMI) flow grade pre-PCI (46.9% vs. 75.0%; p = 0.018), a difference not seen in the overall APEX-AMI study. A multivariate model including baseline features and pexelizumab treatment found anterior MI location and pre-PCI TIMI flow to be significant independent predictors infarct size (p = 0.001), whereas pexelizumab was not (p = 0.29). No death, heart failure, or shock was noted in either substudy group at 90 days.
Conclusions: In a CMR substudy of pexelizumab in MI, baseline TIMI flow grade and anterior location were the only predictors of infarct size, with a reduction of pre-PCI TIMI flow grade 0 by 28%, leading to a 35% reduction in infarct size. (The APEX-AMI Trial; NCT00091637)
Key Words: cardiac magnetic resonance imaging • pexelizumab • infarct size • APEX-AMI trial
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Abbreviations and Acronyms
| | CK = creatine kinase | | CMR = cardiac magnetic resonance | | DE = delayed enhancement | | ECG = electrocardiogram | | LVEF = left ventricular ejection fraction | | MO = microvascular obstruction | | PCI = percutaneous coronary intervention | | STEMI = ST-segment elevation myocardial infarction | | TIMI = Thrombolysis In Myocardial Infarction |
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When available, rapid primary percutaneous coronary intervention (PCI) is the recommended therapy for patients with acute ST-segment elevation myocardial infarction (STEMI). Despite advances in technology and systems to decrease time from presentation to reperfusion, patients continue to suffer from significant morbidity and mortality following STEMI. Myocardial ischemia and reperfusion injury are felt to be important mechanisms underlying poor clinical outcomes (1). Pexelizumab is an anti-C5 complement antibody that was shown in animal studies to reduce infarct size and improve ventricular function in ischemia reperfusion models (2,3). In phase II clinical studies, pexelizumab, when given as a bolus plus infusion, was found to reduce mortality in patients with acute STEMI undergoing percutaneous revascularization. This improvement in mortality, however, was not associated with the expected reduction in infarct size as quantified by creatine kinase (CK)-myocardial band area under the curve up to 72 h (4).
Cardiac magnetic resonance (CMR) allows for high-resolution assessment of infarct size, ventricular volumes, and function as measured by quantified ejection fraction (EF). The gadolinium delayed-enhancement cardiac magnetic resonance (DE-CMR) technique has been shown to be sensitive for myocardial necrosis, allowing visualization of minute amounts of necrosis/scarring as areas of hyperenhancement (5,6), and accurate for identification of both acute and chronic infarction (7–10).
The APEX-AMI (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction) was a large multicenter clinical trial evaluating pexelizumab versus placebo in patients with acute ST-segment elevation undergoing primary percutaneous intervention (11). Given the limitations of current blood biomarker estimates of infarct size and the hypothesis that pexelizumab might improve myocardial healing as well as reduce acute necrosis, we performed a CMR substudy to determine if pexelizumab reduced infarct size and improved ventricular function. No clinical benefit with pexelizumab treatment was recently reported for the APEX-AMI study (11), and the results of the CMR substudy are presented here.
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Methods
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The APEX-AMI study design.
The design and results of the APEX-AMI study have been previously published (12). Briefly, intravenous pexelizumab was compared with placebo administered in a randomized and blinded fashion immediately before primary PCI for electrocardiographically high-risk STEMI patients within 6 hours of symptom onset. Patients were enrolled between July 13, 2004, and May 11, 2006, at 296 sites in 17 countries, with a final enrolled trial population of 5,745 patients. The institutional review board at each participating hospital approved the protocol, and patients were required to provide written informed consent.
CMR substudy design.
Consecutive patients enrolled in the APEX-AMI trial at 5 international sites were screened for inclusion in the CMR substudy. Patients with a prior history of MI, coronary artery bypass surgery, or prior percutaneous intervention were excluded because of potential confounding of infarct size measurement. Additionally, patients with standard metallic contraindications to CMR were excluded. Aside from study medication, patients were treated according to standard of care by investigators, including use of all concomitant medications, procedural techniques, and use of adjunctive devices. Patients underwent 2 dedicated CMR studies, 1 on day 3 to 5 and 1 on day 90 (±1 week) following index primary PCI (Fig. 1).
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Figure 1 APEX-AMI CMR Substudy
(A) Diagram of cardiac magnetic resonance (CMR) study enrollment. (B) Cine-CMR in long- and short-axis. Delayed enhancement CMR demonstrates corresponding areas of infarction, seen as bright areas. LV = left ventricular; MI = myocardial infarction; MRI = magnetic resonance imaging.
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Patient and procedural characteristics.
Standard baseline enrolled patient characteristics such as age, cardiac risk factors, time from symptom onset to presentation, infarct location, and Killip class on presentation were collected. Detailed procedural findings including time to PCI, culprit vessel, pre- and post-Thrombolysis In Myocardial Infarction (TIMI) flow grade, and concomitant therapies were also collected. Coronary angiograms were evaluated at a central core angiographic laboratory (Cleveland Clinic Angio Core Lab, Cleveland, Ohio). Admission electrocardiograms (ECGs) were also evaluated at a core laboratory (Canadian VIGOUR Centre, Edmonton, Alberta, Canada; Duke Clinical Research Institute, Durham, North Carolina) for degree of ST-segment deviation.
CMR imaging.
All images were acquired on 1.5-T scanners using a phased array coil during repeated breath holds (8 to 10 s). The CMR exam consisted of 2 components, cine-CMR for ventricular volumes and function and DE-CMR for infarct size assessment and evaluation of microvascular obstruction (MO). Briefly, cine- and DE-CMR images were obtained in matching short-axis planes (every 8 mm throughout the entire LV) and long-axis planes. Long-axis images were obtained in standard 2-, 3-, and 4-chamber orientations. The cine-CMR was performed using a steady-state free-precession sequence. Typical parameters were repetition time of 3.0 ms, echo time of 1.5 ms; flip angle of 60°; temporal resolution of 35 ms, in plane resolution of 1.7 x 1.4 mm, slice thickness of 6 mm, and 2-mm gap. The DE-CMR was performed using a segmented inversion-recovery sequence (in-plane spatial resolution 1.7 x 1.4 mm; temporal resolution 160 to 200 ms) 10 min after contrast administration (gadolinium 0.15 mmol/kg) (13,14). Inversion times were adjusted in the standard fashion to null viable myocardium, typically 280 to 360 ms. Additionally, imaging was repeated after 10 min to improve detection and confirm areas of MO often termed "no reflow" (Fig. 2). Total time for the CMR evaluation was typically 30 to 40 min.
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Figure 2 Schematic of Cardiac Magnetic Resonance Imaging Evaluation
Planimetry of cine short-axis slices is performed during diastole and systole for ventricular volumes and function. The corresponding delayed enhancement short-axis slices undergo planimetry for infarct size. Microvascular obstruction imaging with repeat delayed enhancement imaging is demonstrated on the last row. Note, within infracted regions, that the areas of microvascular obstruction (dark regions) can be seen on initial delayed enhancement imaging (arrow). These areas fill in with contrast and hyperenhanced (bright areas) with time as seen on repeat delayed enhancement imaging. LV = left ventricular.
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Ventricular Function and Infarct Size Analysis
All CMR images were analyzed in a central core lab (Duke Cardiovascular Magnetic Resonance Center, Durham, North Carolina). All core lab assessments were performed without knowledge or access to treatment assignment, procedural results, or clinical outcomes. Planimetry of myocardial borders on all contiguous short-axis cine images, including papillary muscles, was performed for left ventricular ejection fraction (LVEF) and ventricular volumes (Fig. 2). The LVEF was calculated as follows: (volume at end of diastole – volume at end of systole)/(volume at end of diastole). Similarly, LV mass was measured by planimetry of myocardial borders on all contiguous short-axis DE-CMR images. Once the borders were identified, infarct size was quantified by planimetry of hyperenhanced areas on each short-axis image. Dark areas within infarct regions representing MO were also quantified by planimetry on the first DE-CMR images. Infarct size as a percentage of LV myocardium was calculated by the sum of the volume of all hyperenhanced regions on all slices divided by the sum of the LV myocardial cross-sectional volumes. Interobserver and intraobserver agreement for scar size in the CMR core laboratory using Bland-Altman analysis demonstrated a bias of 1.0% and –0.1%, with a standard deviation of differences of 2.6% and 0.8%, respectively.
Statistical analysis.
For sample size determination, a baseline infarct size for the study population of 15% of the left ventricle with a standard deviation 10% and LVEF of 45% with a standard deviation of 12% was assumed from recent primary percutaneous MI studies (15). Assuming that study patients with acute MI undergoing percutaneous revascularization would obtain successful revascularization and myocardial improvement demonstrated by a 33% decrease in infarct size and 10% increase in LVEF, a sample size of 85 patients was thought to provide 80% power to detect a significant relationship between pexelizumab therapy and improvement at an alpha level of 0.05. Assuming approximately a 10% to 15% dropout rate (e.g., patients lost to follow-up, inability to return for CMR, death, interval implantation of ICD), we anticipated that 100 enrolled patients would be needed to identify improvement in infarct size and/or LVEF with pexelizumab compared with placebo.
Baseline patient characteristics, procedural details, and CMR findings were described according to treatment assignment to pexelizumab or placebo. Data for continuous variables were presented in medians with 25th and 75th percentiles, and categoric variables were presented as frequencies and percentages. Testing for treatment differences was performed with Wilcoxon rank sum tests for continuous variables, and chi-square tests were used for categoric variables.
A general linear multivariate regression model was created to assess the relationship between clinical characteristics and the infarct size on day 3 DE-CMR. Specifically, 3 modeling techniques were used: 1) a model that begins with all the variables and then removes insignificant variables 1 at a time (backward); 2) a model that begins with no variables and adds variables 1 at a time (forward); and 3) a model that begins with all of the variables, then removes variables 1 at a time, and then assesses if an included variable should be removed (stepwise). All 3 modeling techniques were used to see if there might be a difference in results. Candidate variables chosen from baseline and procedural characteristics included age, MI location, pre-PCI TIMI flow grade, hours from symptom onset to randomization, qualifying Killip class, total baseline ST-segment deviation, post-PCI TIMI flow grade, and pexelizumab treatment. Normality assumptions were tested. The dependent variable was normally distributed. The predicted versus model residuals were plotted. There did not appear to be a pattern. A log transformation was used to model time from symptom onset to randomization, and a squared term was used to model total baseline ST-segment deviation. All other continuous factors were modeled linearly. Because the dependent variable for these models' infarct size is continuous, significant predictors from the model are presented by their predicted effect on infarct size, with 95% confidence intervals. All analyses were performed using SAS software (versions 8.2, SAS Institute, Cary, North Carolina).
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Results
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During the APEX-AMI trial, 102 patients consented to be in the CMR substudy at the time of study enrollment. Of these 102 patients, 3 patients were excluded because of history of prior MI or metallic contraindication to CMR after enrollment in the trial. Therefore, 99 patients underwent CMR on median day 3.0 (interquartile range 2.0 to 4.0). Two patients completed cine-CMR but were unable to undergo DE-CMR secondary to claustrophobia and difficulty with breath holds. Consequently, infarct imaging was performed in 97 patients at baseline. After discharge, 16 patients declined follow-up DE-CMR, which was performed in 83 patients at median day 90 (Fig. 1).
Patient characteristics.
The baseline characteristics of the entire APEX-AMI study population, of the total CMR substudy population, and by randomized treatment assignment in the CMR substudy are presented in Table 1. Patients in the main APEX-AMI study had ST-segment deviation patterns similar to those of patients enrolled in the CMR substudy, and patients in both groups had similar times from symptom onset to enrollment. Patients in the CMR substudy tended to have Killip class I symptoms on presentation compared with the overall APEX population, (95% vs. 89.4%; p = 0.069).
In general, the patients in the 2 treatment groups (placebo vs. pexelizumab) of the CMR substudy had similar baseline characteristics. The median age of the overall enrolled population was 60 years, and 16% were female. Time from symptom onset to enrollment was similar between pexelizumab- and placebo-treated patients (median 2.6 h vs. 2.5 h; p = 1.0). Notably, systolic blood pressure (134.5 mm Hg vs. 140 mm Hg; p = 0.73), Killip class I (92% vs. 98%; p = 0.19), and the degree of ST-segment deviation on baseline ECG (anterior 15 mm vs. 12.5 mm, p = 0.19; high-risk inferior 13.3 mm vs. 15.8 mm, p = 0.21) were similar between pexelizumab- and placebo-treated patients.
Procedural characteristics.
The procedural characteristics by treatment assignment are presented in Table 2. Once randomized, patients in both groups were taken promptly, with slightly longer time to cardiac catheterization, for revascularization (0.63 h vs. 0.47 h; p = 0.025) in pexelizumab- compared with placebo-treated patients. The infarct-related artery was similar between groups, with involvement of the left anterior descending artery in 60% versus 61.9% (p = 0.90) of pexelizumab- and placebo-treated patients, respectively. Importantly, rates of pre-intervention TIMI flow grade 0 were significantly higher in placebo-treated patients compared with pexelizumab-treated patients (75% vs. 46.9%; p = 0.005). Of note, this difference in pre-intervention TIMI flow grade 0 was not observed in the overall APEX-AMI study: placebo (65.2%) and pexelizumab (63.5%). The TIMI flow grade 3 post-intervention was high in both pexelizumab- and placebo-treated patients in the CMR substudy (92% vs. 85.7%; p = 0.320). Core lab-measured >70% ST-segment resolution following percutaneous revascularization was present in 58.7% of pexelizumab-treated patients compared with 40% of placebo-treated patients (p = 0.106).
CMR findings.
The main findings from the CMR are presented in Table 3. On baseline CMR performed 3 to 5 days following STEMI, the median infarct size in the entire study group was 13.7% of the LV. Pexelizumab treatment was associated with significant reduction in infarct size on baseline CMR (or median 10.5 vs. 16.2 % LV; p = 0.022), higher LVEF (50.3% vs. 46.2%; p = 0.0376), and a trend of less MO (29.2% vs. 46.9%; p = 0.072) compared with placebo-treated patients. Although routine serial biomarker analysis was not mandated during the APEX-AMI study, investigators reported that peak CK levels were recorded. Pexelizumab-treated patients had more than 50% lower reported peak CK values (1,972 mg/dl vs. 922 mg/dl; p = 0.03) compared with placebo-treated patients.
Follow-up CMR performed on day 90 also found that pexelizumab-treated patients had significantly smaller infarct size (median 5.9 vs. 12.4 % LV; p = 0.015) compared with placebo-treated patients. Additionally at this time, pexelizumab-treated patients had significantly higher LVEF (53.9% vs. 49.3%; p = 0.026) compared with placebo-treated patients. It should be noted that differences in baseline findings likely accounted for differences at 90 days because the change in LVEF and infarct size between the 2 time points was not significantly different between the groups (Table 3). No clinical events (death, shock, heart failure, or recurrent MI) were noted in any of the CMR substudy patients during a 6-month follow-up.
Predictors of baseline infarct size.
Candidate variables, including age, MI location, pre-PCI TIMI flow grade, hours from symptom onset to enrollment, qualifying Killip class, total baseline ST-segment deviation, post-PCI TIMI flow, and pexelizumab treatment, were included in regression modeling to determine predictors of baseline infarct size. Poor pre-PCI TIMI flow grade (0/1) and anterior location of myocardial infarct were the only independent predictors of baseline infarct size (p < 0.0001). Pexelizumab treatment was not a predictor of infarct size (p = 0.29) (Table 4). The predicted baseline infarct size based on pre-PCI TIMI flow and location of MI is presented in Table 5.
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Discussion
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The principal finding from this substudy of the APEX-AMI trial is smaller infarct size at baseline and at 90 days and related improved LVEF determined by CMR with pexelizumab treatment compared with placebo among patients undergoing primary PCI for acute MI. Additionally, MO and ventricular volumes measured by CMR also trended toward improvement in the pexelizumab group. In contrast, the overall APEX-AMI trial of 5,745 patients found no clinical effect on all-cause mortality or heart failure in patients treated with pexelizumab compared with placebo at the time of primary PCI. Patients received rapid reperfusion with guideline-based care during the conduct of the trial, with an overall observed 30-day mortality rate of only 4% (12).
The CMR substudy findings, in conjunction with those from angiographic and ECG data, do provide an important perspective on reperfusion in acute MI as reflected in infarct size and ventricular function. Several studies have used radionuclide imaging for infarct size measurement in patients undergoing percutaneous intervention for acute MI. Recently, these radionuclide studies reported the predictors of larger infarct size to be anterior location, epicardial artery perfusion before and after angioplasty, male sex, time to reperfusion, previous acute MI, and failed thrombolysis (15). These studies are limited by variable inclusion criteria (allowing prior thrombolysis in some studies) and variable time to infarct size imaging ranging from 5 to 35 days post-infarct.
The present study represents a select cohort of patients in a large primary PCI acute MI study at multiple international sites undergoing primary PCI with robust assessment, including core lab-quantified ECGs, angiograms, and CMR. Infarct size, MO, and ventricular function evaluation were readily imaged with standardized CMR techniques. Despite high-risk characteristics on ECG, delivery of rapid effective reperfusion resulted in a small median infarct size that was only 13.7% of the LV and a median baseline LVEF that was 48.3% on CMR (Table 3). Even in this population, DE-CMR was able to detect modest but statistically significant differences in infarct size (approximately 6% LV) and LVEF (approximately 5%). The observed infarct size reduction was associated with a 28% reduction in pre-PCI TIMI flow grade 0 and trends toward improvement in post-PCI TIMI flow grade 3 and post-PCI ST-segment resolution. Hence, this study demonstrates that routine CMR examination in patients with acute MI at baseline and follow-up is a feasible technique that allows for sensitive evaluation of both infarct size and ventricular function. Additionally, CMR helps in linking surrogate measures in the physiologic chain of events occurring during reperfusion for acute MI from baseline ST-segment deviation, pre-PCI TIMI flow grade, post-PCI TIMI flow, ST-segment resolution, and baseline infarct size on CMR to final 90-day LV function. The current study confirms that anterior location and poor pre-PCI TIMI flow grade (0/1) are associated with larger baseline infarct size.
There is discordance between the observed findings from the CMR substudy and the clinical findings from the APEX-AMI trial. There are 3 possible explanations: 1) pexelizumab may reduce infarct size, in both this subset and the overall APEX-AMI trial, but had some counterbalancing effect that prevented an overall clinical benefit; 2) CMR may have been inaccurate in assessing infarct size, and thus, it was incorrectly concluded that infarct size was reduced in the substudy; or 3) given the selective bias inherent in subgroup analysis in a population of survivors, there may have been smaller infarcts in the pexelizumab group in the substudy population because of chance without a similar effect in the overall trial.
We believe the third explanation is most likely. Other results support the CMR findings of a smaller infarct size. All available CMR measures performed on both acute and chronic scans, including infarct size, MO, ventricular volumes, and LVEF, favor the pexelizumab-treated cohort. Although serial biomarker measurements were not mandated in the current study, peak measured CK levels in this population also were significantly lower in the pexelizumab compared with placebo patients. Therefore, both internal and external measures in the CMR substudy population support the CMR findings. However, data suggest that the CMR substudy population may have been imbalanced, by chance, in favor of pexelizumab.
Specifically, the angiographic procedural findings provide insight into the observed differences in infarct size and subsequent ventricular function. Despite similar amounts of ST-segment deviation on baseline ECG and similar time from symptom onset to revascularization, pexelizumab-treated patients had significantly lower rates of TIMI flow grade 0 on presentation (46.9% vs. 75%; p = 0.018) compared with placebo-treated patients. Because the pexelizumab study drug was given only minutes before the angiogram and the drug was not expected to effect reperfusion itself, this difference in baseline TIMI flow grade is likely due to chance. In fact, multivariable modeling including pexelizumab treatment found only anterior infarct location and pre-PCI TIMI flow grade to be significant predictors of infarct size. This difference in pre-PCI TIMI flow grade translated into post-procedural TIMI flow grade 3 rates and core lab ST-segment resolution that also trended higher in pexelizumab-treated patients compared with placebo-treated patients. Therefore, a difference in myocardial perfusion rates as observed with pre-PCI TIMI flow grade rates on angiogram may explain a difference in infarct size and subsequent ventricular function observed in the CMR substudy.
Notably, the CMR substudy patients represented a selected population within the overall APEX-AMI study. Patients enrolled in the CMR study did not have prior MI, and importantly, had to survive and be clinically stable to undergo CMR on days 3 to 5. This excluded patients with significant cardiogenic shock and those requiring long-term invasive support. In contrast to the CMR substudy, there was no difference in the observed pre-PCI TIMI flow grade or the peak reported CK levels in the overall APEX-AMI trial. Therefore, although we cannot exclude a treatment effect with pexelizumab in the CMR substudy, the findings likely represent a chance observation in a select population not present in the overall study.
As with any biomarker or imaging measure, CMR with cine and DE cannot in isolation be used to reliably determine effects on clinical outcomes. Although some initial data regarding clinical outcomes are emerging (16), further research is required to understand the relationship between findings and clinical outcomes. Nevertheless, in this CMR study, pexelizumab-treated patients, likely by chance, were found to have lower rates of "closed arteries" with pre-PCI TIMI flow grade 0 at presentation, leading to a small but statistically significant reduction in infarct size and improvement in LVEF as measured by CMR. These findings highlight the caution required in interpreting results from pilot and early phase studies and underscore the importance of multiple measures of physiologic and clinical effect to understand treatments. CMR is a robust and sensitive technique that provides important mechanistic information on the effect of therapies aimed at myocardial protection. Future studies on myocardial protection should consider the use of CMR as part of a systematic approach including multiple measures of reperfusion to provide a comprehensive evaluation of effect.
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Footnotes
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The APEX-AMI trial was jointly funded by Procter & Gamble Pharmaceuticals and Alexion Pharmaceuticals. Drs. Van de Werf, Armstrong, and Granger received research grants from the trial sponsors. Members of the Steering Committee received honoraria for their participation.
* Reprint requests and correspondence: Dr. Manesh R. Patel, Box 3850 Medical Center, Duke University, Durham, North Carolina 27710 (Email: manesh.patel{at}duke.edu).
Manuscript received November 7, 2008;
revised manuscript received September 1, 2009,
accepted September 8, 2009.
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Abstract
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