Pharmacoutilization and costs of osteoarthritis: changes induced by the introduction of a cyclooxygenase-2 inhibitor into clinical practice

P. Russo, A. Capone2, E. Attanasio1, G. Baio3, M. Di Martino4, L. Degli Esposti4, F. Marchetta5, S. Buda4, E. Degli Esposti6 and L. Caprino1

Department of Human Physiology and Pharmacology and
1 Department of Experimental Medicine and Pathology, University of Rome ‘La Sapienza’,
2 Outcomes Research Engineering Consulting, Rome,
3 EPRIS Research Group, University of Siena, Siena,
4 Clicon S.r.l., Health, Economics, and Outcome Research, Ravenna,
5 Sant'Orsola Malpighi Hospital, Bologna and
6 Local Health Unit 110, Ravenna, Italy


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conflict of interest
 References
 
Objective. To establish whether the introduction of a cyclooxygenase-2 inhibitor has led to changes in pharmacoutilization in the treatment of osteoarthritis (OA) in clinical practice.

Methods. Administrative and general practice databases were cross-linked to analyse the use of non-steroidal anti-inflammatory drugs (NSAIDs) and gastroprotective agents (GPAs) before and after the introduction of rofecoxib. Costs of treatment and costs of hospitalization for gastrointestinal events were also considered.

Results. A total of 3090 patients were evaluated. A significant reduction in the use of GPAs in the rofecoxib group was observed, corresponding to reductions of 64 and 59.7% compared to NSAIDs among patients in incident and prevalent cases respectively. The weighted mean daily cost of therapy with rofecoxib in incident cases was \#8364;1.88, 7.4% lower than that of NSAIDs (\#8364;2.03), and in prevalent cases it was \#8364;1.87, 28.1% higher than that of NSAIDs (\#8364;1.46). Although the rate of hospitalization was similar, there was an additional daily cost per patient of \#8364;186.6 for patients being treated with NSAIDs and \#8364;21.6 for those being treated with rofecoxib.

Conclusions. The cyclooxygenase-2 inhibitor rofecoxib determined substantial changes in the pharmacoutilization and costs of OA.

KEY WORDS: Osteoarthritis, NSAIDs, COX-2-specific inhibitors, Clinical practice, Costs.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conflict of interest
 References
 
Among rheumatic diseases, osteoarthritis (OA) is decidedly the most frequent manifestation, its prevalence being correlated to the rising mean age of the population [1]. This is a chronic, degenerative and disabling disease that reduces the quality of life of patients [24]. Analysis of the costs generated by OA is a topic of growing importance, primarily because OA is one of the main reasons for temporary and permanent disability [5, 6], but also because of its prevalence, which in Italy is estimated to be between 10 and 18% [7, 8], in line with statistics recorded in other industrialized countries [9].

Symptomatic treatment of OA is based on the widespread use of a group of efficacious substances known as non-steroidal anti-inflammatory drugs (NSAIDs). Because of their low selectivity in inhibiting cyclooxygenase (COX) 1 and 2, however, conventional NSAIDs can induce side-effects in the upper gastrointestinal (GI) tract, some of them minor (dyspepsia, heartburn, nausea, abdominal pain, diarrhoea) but others more serious, including perforation, ulceration and bleeding [10, 11]. For this reason, the treatment of OA with NSAIDs is frequently associated with the prescription of gastroprotective agents (GPAs), typically H2-receptor antagonists, proton pump inhibitors, antacids, misoprostol and sucralfate. In European countries, the rate at which GPAs are coprescribed varies from 21% in Great Britain [12] to 50% in Spain [13]. Levels of coprescription recorded in Italy are similar to the figure for Spain [7]. The use of GPAs has the effect of increasing the overall cost sustained by local health units in the treatment of OA.

New anti-inflammatory compounds have come onto the market recently, namely the coxibs (celecoxib and rofecoxib), formulated specifically to inhibit COX-2, which is thought to be the principal enzyme involved in the production of inflammatory mediators [14]. Theoretically, the pharmacodynamics of these substances suggests that they should produce an anti-inflammatory effect similar to that of conventional NSAIDs but with a better GI tolerability profile [1518]. Coxibs ought therefore to have a favourable impact on the overall value of the economic resources expended on the treatment of OA, in terms of reducing both the use of GPAs and the incidence of clinically relevant GI side-effects. Recent publications have shown initial evidence of a reduction in the use of GPAs during the course of treatment with rofecoxib [19, 20].

The objective of this study was to establish whether and to what extent the introduction of a COX-2 inhibitor has induced changes in pharmacoutilization related to the treatment of OA in a population observed under the real-world conditions of clinical practice. The evaluation was made from the perspective of a local health unit [Azienda Unità Sanitaria Locale (AUSL)], by cross-linking information stored in different databases.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conflict of interest
 References
 
Administrative data and clinical data were cross-linked to analyse the use of drugs in the treatment of OA. Thus, all prescriptions for conventional NSAIDs and GPAs in the period preceding and following the introduction of the first COX-2 inhibitor available in Italy (rofecoxib) were examined and compared in the same population of general practitioners (GPs) and the patients registered in their lists. To complete the evaluation, we analysed hospital admissions for GI events experienced by patients treated with conventional NSAIDs or rofecoxib, and the overall costs sustained by the AUSL of Ravenna (central north Italy).

Data sources
The first step was to examine data recorded in a database structured to enable the gathering of information from general clinical practice. This database contains information generated electronically from a representative sample of 30 GPs, corresponding to 9.4% of the total number of GPs operating under the AUSL of Ravenna. All these GPs are equipped with a computerized system responding to predetermined technical parameters so as to allow the entry and automatic transmission of data to a dedicated server. Each single prescription given by any GP is recorded and contributes to a longitudinal health record for the individual patient. The GP database also contains information characterizing the patient, such as smoking habit, body mass index, cardiovascular risk profile and the presence of concomitant diseases.

The general practice data were then cross-linked with data from the AUSL databases, which are structured to serve administrative purposes (registry, pharmaceutical and hospital databases).

The AUSL is a body delegated by the Italian National Health Service to deliver health-care services to a population living in a specific geographical area, generally a province. The AUSL of Ravenna, being a financial terminal of the National Health Service, has set up an information network to measure the volume of expenditure on reimbursed drugs dispensed to registered patients by all pharmacies in the district. The pharmaceutical database, in which every reimbursable prescription received from pharmacies is recorded, has been operational since 1 January 1996 and contains the following information: (i) the National Health number of the patient; (ii) the roll number of the prescribing physician (GP); (iii) the Anatomical Therapeutic Chemical (ATC) code for the drug purchased; (iv) the number of packs prescribed; (v) the number of units per pack and relative dosage; (vi) the unit cost per pack; and (vii) the prescription date. Accordingly, a retrospective analysis of any event that occurred to an individual patient can be conducted. Using the patient's National Health number, it is possible to formulate targeted interrogations cross-linked between the registry and hospital database (also operational since 1 January 1996) and the pharmaceutical or GP database. Thus, the longitudinal picture of information on individuals can be completed by adding in the date of birth, gender, and any record of hospitalization for specific diseases [identified according to the International Classification of Diseases, Ninth Revision (ICD-9)].

Study design
The cohort of patients registered with the 30 GPs consisted of 33 898 individuals, corresponding to 9.7% of the entire population registered with the AUSL of Ravenna (about 350 000 residents). All patients evaluated had a confirmed diagnosis of OA (according to the ICD-9 code in the GP database) on the basis of a longitudinal clinical evaluation.

The analysis of pharmacoutilization relative to the period preceding the introduction of rofecoxib included all patients with a confirmed diagnosis of OA who had been prescribed a conventional NSAID, with or without GPA comedication, during the period from 1 January 1999 to 30 June 2000 (Fig. 1Go). In the period subsequent to the introduction of rofecoxib (datable to 1 July 2000), the analysis included all patients with a confirmed diagnosis of OA who were prescribed rofecoxib, with or without GPA comedication, in the period from 1 July 2000 to 30 June 2001 (Fig. 1Go).



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FIG. 1. Outline of study comparing pharmacoutilization in patients with OA treated with rofecoxib and conventional NSAIDs. Dashed lines represent the period of retrospective observation to identify the prevalent cases. Solid lines represent the period of prospective observation for each treatment group.

 
To identify incident and prevalent cases among all patients with OA included in the study, the analysis also took account of prescriptions for conventional NSAIDs received in the 18 months preceding the observation period for each treatment group.

GPAs were included in the pharmacoutilization analysis only when records showed multiple prescriptions for conventional NSAIDs or rofecoxib, both in prevalent cases and in the incident cases. To prevent the possibility of prescription-related ambiguities acting as a potential confounding factor, all patients who had received a single prescription for NSAIDs/rofecoxib were excluded.

Cost data
In evaluating the expenditure sustained by the AUSL, account was taken of the costs incurred in purchasing drugs and those induced by hospital admissions due to GI complications in patients who had been prescribed conventional NSAIDs or rofecoxib in accordance with the inclusion criteria. The average daily cost of pharmacological therapy was determined according to the mean number of tablets taken by patients per day of treatment. Hospitalization codified by the following ICD-9 codes of primary discharge diagnosis: peptic ulcer, 531–534; haematemesis, 578.0; melaena, 578.1; and GI bleeding, 578.9. Hospitalization costs included expenditure in respect of hospital stay, instrumental procedures needed to confirm the diagnosis of a GI injury (abdominal X-ray, GI endoscopy, colonoscopy) and specific therapies (drugs, transfusions, and surgery if needed). All these costs were grouped for any hospitalized patient and classified by ‘diagnosis-related group’, whereby a defined national tariff of reimbursement is assigned. Details of specialist consultations and gastroscopies conducted at sites other than hospitals had not been recorded systematically, and because they were not always available they were excluded from the computation.

Statistical methods
The effect of continuous variables is expressed as mean±S.D. Statistical significance between proportions was calculated using Pearson's {chi}2 test or, for two frequencies, using the z-test.

The statistical significances of differences between averages were calculated using the independent-samples t-test. All P values quoted are two-sided. P values less than 0.05 were considered significant.

The strength of the relationship between the type of anti-inflammatory drug (NSAIDs/rofecoxib) and the outcome variable (use of GPAs) was measured by computing the relative reductions, their corresponding 95% confidence intervals and P values for different categories of patients, taking NSAID therapy as the reference category. Relative reductions were derived from frequency tables and adjusted for potential confounders (age, gender, smoking habits, previous hospitalizations for GI events, prescription of corticosteroids, number of different NSAIDs used) using logistic regression models [21].

All statistical analyses were performed using SPSS for Windows version 10.1 (SPSS, Chicago, IL, USA).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conflict of interest
 References
 
The study population numbered 3090 patients affected by OA and treated with anti-inflammatory drugs. Within this overall figure, 2944 were treated with NSAIDs, of which 2059 (70%) were prevalent cases and 885 (30%) were incident. The number of patients exposed to rofecoxib was 487, with a ratio of prevalence and incidence identical to those observed in the NSAID group (Fig. 1Go).

Table 1Go indicates the demographic characteristics of patients in the two treatment groups. A comparison reveals statistically significant differences. Patients treated with rofecoxib were older on average, with an age range predominantly represented by the group over 65 yr. Whereas the male/female ratio was in line with epidemiological data for OA, there was a significant preponderance of women in the rofecoxib group compared with the group treated with conventional NSAIDs. On average, patients in the rofecoxib group received a significantly greater number of different anti-inflammatory drugs (2.3±1.2) than those in the conventional NSAID group (1.61±0.9). Moreover, the frequency of refilled treatments (multiple prescriptions) was significantly higher for patients on rofecoxib than for patients on conventional NSAIDs.


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TABLE 1. Demographic characteristics of the two groups of patients diagnosed as having osteoarthritis

 
Table 2Go illustrates the distribution of prescriptions for conventional NSAIDs before and after the introduction of rofecoxib. Considered overall, the availability of the new drug produced no significant change in the use of conventional anti-inflammatories, with the exception of oxicam derivatives, for which a significant reduction was recorded following the introduction of rofecoxib (P=0.003).


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TABLE 2. Distribution of prescriptions for conventional NSAIDs before and after the introduction of rofecoxib

 
Table 3Go shows the number of prescriptions for GPAs, by class, for the two groups. The distributions showed a significant difference that was attributable to the increased number of prescriptions of proton pump inhibitors and misoprostol in the group of patients treated with rofecoxib.


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TABLE 3. Distribution of prescriptions for GPAs in the two treatment groups

 
The introduction of rofecoxib triggered a relevant change in the pharmacoutilization of GPAs. The findings show a sizeable, statistically significant reduction in the frequency with which GPAs were coprescribed (Table 4Go). In particular, there was a relative reduction among incident cases of 64%, corresponding to an absolute difference of 27.2 percentage points, whereas among prevalent cases the relative reduction was 59.7%, corresponding to an absolute variation of 26.5 percentage points.


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TABLE 4. Frequencies and variations observed in coprescription of GPAs for patients receiving multiple prescriptions for anti-inflammatory drugs

 
The size of the relative reduction in coprescription of GPAs among patients treated with rofecoxib remained substantially stable even after adjustment was made for the main acknowledged GI injury risk factors associated with conventional NSAIDs [22, 23] by conducting a multivariate logistic regression analysis. The reduction in GPA coprescription varied between 54 and 96% depending on age, gender, smoking habits, previous hospitalizations for GI events, prescription of corticosteroids and the number of different NSAIDs used (Table 5Go).


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TABLE 5. Crude and adjusted relative reductions in the use of GPAs among patients receiving multiple prescriptions for anti-inflammatory drugs, computed by multivariate logistic regression analysis

 
Table 6Go reports the costs incurred by the AUSL solely in respect of drug therapy for patients receiving multiple prescriptions. Whatever the classification (incident or prevalent cases) of patients for whom no gastroprotective treatments were prescribed, those taking rofecoxib always generated a significantly higher mean daily cost to the health-care provider than those taking conventional NSAIDs (incident cases, \#8364;1.62 vs \#8364;0.89; prevalent cases, \#8364;1.61 vs \#8364;0.78). By contrast, in the remaining patients the weighted mean daily cost correlated with the frequency of GPA coprescription was always lower for patients taking rofecoxib than for those taking conventional NSAIDs (incident cases, \#8364;0.51 vs \#8364;1.52; prevalent cases, \#8364;0.55 vs \#8364;1.03).


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TABLE 6. Comparison between unweighted and weighted average daily costs attributable to symptomatic treatment of OA with conventional NSAIDs and rofecoxib in patients receiving multiple prescriptions

 
Considered overall, it emerges that for incident cases the daily expenditure on patients of the rofecoxib group was 7.4% less than expenditure on patients in the conventional NSAID group (\#8364;1.88 and \#8364; 2.03 respectively). Conversely, and notwithstanding the reduced use of GPAs, the weighted mean daily cost of treatment with rofecoxib in prevalent cases was 28.1% higher than the cost of treatment with conventional NSAIDs (\#8364;1.87 vs \#8364;1.46).

In addition to expenditure on drugs, the present study examined the cost generated by hospitalizations for GI events that occurred during the course of treatment with conventional NSAIDs and rofecoxib (Table 7Go). Although there were no differences between the two treatment groups with regard to the incidence of hospitalizations (approximately 6.1 per 1000 patient-yr), patients in the NSAID group showed a lower frequency of several GI injury risk factors (mean age, average number of anti-inflammatory drugs used and previous hospitalizations for GI events), but a higher GPA coprescription rate, a longer length of hospital stay (16.8 vs 3.3 days with NSAIDs and rofecoxib respectively) and consequently a higher overall cost of hospitalization. This generated an additional daily cost over and above the mean weighted cost of pharmacological treatment of OA, quantifiable at \#8364;186.6 for patients taking conventional NSAIDs and \#8364;21.6 for patients taking rofecoxib.


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TABLE 7. Comparison between demographic and therapeutic characteristics of patients hospitalized for GI events

 


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conflict of interest
 References
 
The present study represents one of the first European instances of experience relating to the combined use of administrative and general practice databases in providing a detailed description of symptomatic treatment for osteoarthritis. In addition, it was possible to evaluate the impact of expenditure deriving from the introduction of a COX-2 inhibitor, rofecoxib, using data from clinical practice in a real-world population setting.

The analyses of administrative and general practice databases conducted previously by our group have proved useful in studying the use of drugs in other therapeutic areas, providing results that are methodologically and statistically reliable [2427].

In terms of pharmacoutilization, the results suggest that the prescriptive behaviour of physicians is generally creditable. The selection criteria adopted by GPs in prescribing a treatment for OA have not changed with the introduction of rofecoxib. The proportional relationship between incidence and prevalence has stayed the same, and only 11.6% of patients previously treated with conventional NSAIDs switched to a treatment with the new drug. Moreover, the patients who switched have often been previously treated with conventional NSAIDs that are supposedly associated with a higher risk of GI damage (oxicam derivatives) [23, 2830].

Compared with the NSAID group, patients who started treatment on rofecoxib were generally classifiable as having a significantly greater number of NSAID-induced GI injury risk factors (mean age, preponderance of patients over 65 yr, number of different anti-inflammatory drugs used) and, once on treatment, registered a considerably higher percentage of multiple prescriptions (83.1 vs 63.7%, P < 0.001). This latter finding, probably a sign to some extent of better compliance, might be related to the tolerability and effectiveness of rofecoxib, at least in the first instance.

The availability of rofecoxib has not produced appreciable change in the approach to the prescription of conventional NSAIDs for OA sufferers, but it emerges from the data that a dramatic change has occurred in the use of GPAs. The overall reduction in use has been notably significant across the board, with a mean value quantifiable at around 60% (95% confidence interval 49–72%, P < 0.001). Importantly, the reduced coprescription of GPAs was confidently confirmed by logistic regression analysis, conducted in order to control the confounding effect of the various NSAID-induced GI injury risk factors for each item of reduction data observed. Again, it is significant that the pattern of the reduction in coprescription presented a trend of increasing with the rise of the number of anti-inflammatory drugs taken (from 54% in patients who took one NSAID to 69% in those taking more than two). A similar pattern was also observed when we considered the use of corticosteroids (from 63% relative reduction in the case of non-users to 72% among users).

Comparing the univariate with the multivariate analysis, it can be noted in the case of patients taking rofecoxib that the presence of a greater number of NSAID-induced GI injury risk factors led to a conservative evaluation of the reduction in GPA use compared with that recorded in the absence of such a bias. Indeed, the crude relative reductions were systematically less than the adjusted reductions for almost all of the risk factors considered (Table 5Go).

Another noteworthy element is provided by the comparison of the distributions of GPAs by class in the two treatment groups. Among patients taking rofecoxib, there was a shift in therapeutic preferences favouring proton pump inhibitors and misoprostol over H2-receptor antagonists and sucralfate. This trend is consistent with recent findings of evidence-based medicine [3133]. However, the shift might have contributed to an underestimation of the weighted average daily cost of treatment with conventional NSAIDs, since the cost of purchasing proton pump inhibitors and misoprostol is higher than that of the H2-receptor antagonists and sucralfate.

With regard to economics, the figures show that the mean expense for rofecoxib was around twice that of conventional NSAIDs, but also that the reduced consumption of GPAs observed in incident cases completely offset this higher differential outlay, bringing a net reduction of 7.4% in the weighted average expenditure sustained by the AUSL. In prevalent cases, on the other hand, the reduced consumption of GPAs, albeit statistically important, was sufficient to cover the higher cost of the new drug only in part (approximately 49%). However, the net increase in weighted average expenditure was appreciably less than would at first have been foreseeable without any reduction in the coprescription of GPAs (28 vs 207%).

In contrast to the situation observed with rofecoxib, the average cost of anti-inflammatories in the conventional NSAID group for patients who received a GPA was significantly higher in comparison with patients for whom no GPA was prescribed (incident cases, \#8364;1.03±0.55 vs \#8364;0.89±0.16, P < 0.001; prevalent cases, \#8364;0.84±0.11 vs \#8364;0.78±0.23, P < 0.001). This might be explained, in the light of specific therapy requirements, by the use of higher doses and/or a greater number of different NSAIDs, which is allowed when a GPA is coprescribed.

Besides analysing the expenditure on drug therapy alone, the study also highlighted certain economic benefits associated with the prescription of rofecoxib by evaluating the impact of hospitalization costs attributable to GI complications. The incidence of hospitalization for GI events was the same for the two groups of patients. Normally this outcome would have been evaluated by multivariate analysis, as for the reduction in coprescription of GPAs, adjusting for differences in the number of NSAID-induced GI injury risk factors present in the two groups; unfortunately this was not possible because of the reduced sample size overall considered.

Nonetheless, analysis of the data showed clinical and economic differences between the two groups, even if these were not statistically significant. From a clinical point of view, only one of the three hospitalized patients in the rofecoxib group was exposed exclusively to rofecoxib; the other two were also exposed to conventional NSAIDs (two different drugs each). Among patients treated with conventional NSAIDs, the mean length of hospital stay was some 13 days longer than for patients treated with rofecoxib (although the latter patients presented more GI injury risk factors and received fewer GPAs). This may be related to the less serious nature of GI events in patients treated with rofecoxib. From the economic point of view (maintaining a conservative position on the attribution of hospitalizations related to rofecoxib), there was a difference in expenditure between the two groups that revealed a real increase in the cost of treatment with conventional NSAIDs, amounting to \#8364;165 net per day.

The present study was limited mainly by the number and incidence of hospitalizations for serious GI events. Whereas the duration of the study period and the size of the samples provided enough statistical power to allow us to evaluate the reduction in the use of GPAs, these parameters were not broad-based enough to allow a full analysis of hospital admissions. Considering that the incidence of hospitalizations documented by other authors ranges between 0.5 and 1.3% [3437], a full study of these events and the related costs would perhaps require a longer follow-up period, and surely a wider sample. This being the case, findings relating to the cost of adverse GI events leading to hospitalization need confirmation.

Another limitation is that this was not a full cost analysis study. The economic evaluation focused on costs directly related to the disease, such as medication and hospitalization costs. Indeed, the overall direct costs have many different elements, although those considered in this study account for the greater part of them.

The purpose of this study was to evaluate the possible effects that the introduction of a new anti-inflammatory drug might have on pharmacoutilization and expenditure for the AUSL in treating osteoarthritis. Consequently, certain elements of information regarding the clinical condition of patients were examined only in part (e.g. severity of pathology and efficacy of treatment), and there was no evaluation of cost-effectiveness. However, these questions are outside the scope of the present study.

In conclusion, the cross-linked analysis of information stored in administrative and general practice databases enabled us to build up a detailed picture of the changes in OA-related pharmacoutilization that occurred after the introduction of rofecoxib. In patients treated with rofecoxib, we observed a considerable reduction in the prescription of GPAs used to treat and prevent NSAID-induced GI side-effects. This change in the prescriptive approach to treatment had a significant impact on the average daily cost of OA-related health-care.


    Conflict of interest
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conflict of interest
 References
 
The authors have declared no conflicts of interest.


    Acknowledgments
 
This study was made possible thanks to the cooperation of 30 GPs operating in the province of Ravenna. Special thanks are due to Dr Gianni Cortesi for his assistance.


    Notes
 
Correspondence to: P. Russo, Institute of Pharmacology (Department of Human Physiology and Pharmacology), University of Rome ‘La Sapienza’, P. le A. Moro, 5-00185, Italy. E-mail: pierluigi.russo{at}uniroma1.it Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conflict of interest
 References
 

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Submitted 2 August 2002; Accepted 11 December 2002





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