Departments of 1 Molecular Physiology and Biophysics and 2 Surgery, and 3 Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615
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ABSTRACT |
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This study was aimed at assessing the role of carotid body function in neuroendocrine and glucoregulatory responses to exercise. The carotid bodies and associated nerves were removed (CBR, n = 6) or left intact (Sham, n = 6) in anesthetized dogs >16 days before experiments, and infusion and sampling catheters were implanted. Conscious dogs were studied at rest and during 150 min of exercise. Isotopic dilution was used to assess glucose production (Ra) and disappearance (Rd). Arterial glucagon was reduced in CBR compared with Sham at rest (29 ± 3 vs. 47 ± 3 pg/ml). During exercise, glucagon increased more in Sham than in CBR (47 ± 9 vs. 15 ± 2 pg/ml). Cortisol and epinephrine levels were similar in the two groups at rest and during exercise. Basal norepinephrine was similar in CBR and Sham. During exercise, norepinephrine increased by 432 ± 124 pg/ml in Sham, but by only 201 ± 28 pg/ml in CBR. Basal arterial plasma glucose was 108 ± 2 and 105 ± 2 mg/dl in CBR and Sham, respectively. Arterial glucose dropped by 10 ± 3 mg/dl at onset of exercise in CBR (P < 0.01) but was unchanged in Sham (decrease of 3 ± 2 mg/dl, not significant). Basal glucose kinetics were equal in Sham and CBR. At onset of exercise, Ra and Rd were transiently uncoupled in CBR (i.e., Rd > Ra) but were closely matched in Sham. In steady-state exercise, Ra and Rd were closely matched in both groups. Insulin was equal in the basal period and decreased similarly during exercise. These studies suggest that input from the carotid bodies, or receptors anatomically close to them, 1) is important in control of basal glucagon and the exercise-induced increment in glucagon, 2) is involved in the sympathetic response to exercise, and 3) participates in the non-steady-state coupling of Ra to Rd, but 4) is not essential to glucoregulation during sustained exercise.
glucagon; insulin; glucose production
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INTRODUCTION |
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THE EXERCISE-INDUCED INCREASE in muscle glucose uptake would result in hypoglycemia if it were not matched by a similar increase in hepatic glucose production. Hypoglycemia does not normally occur, since exercise initiates neural and hormonal responses that aggressively oppose decrements in arterial blood glucose (21). The signal(s) that triggers this neuroendocrine response is not well understood. The generally tight control of arterial blood glucose has led to the hypothesis that the signal that triggers the glucoregulatory response to exercise is directed at the feedback control of arterial blood glucose. This hypothesis is supported by the demonstration that changes in blood glucose that can barely be detected experimentally elicit a robust glucoregulatory response during exercise (5, 9, 22). One must postulate a means of sensing a signal proportional to glucose levels in the arterial circulation for such a feedback loop to be effective. In a recent study, we showed that the response to a moderate hypoglycemia due to insulin infusion was blunted by carotid body resection in the dog. This is consistent with studies in vitro and in situ that show that the carotid bodies are sensitive to blood glucose (3, 4, 11). The carotid bodies are heavily perfused and rich in neural afferents (18). Moreover, stimulation of the carotid bodies by means of hypoxia (27) or NaCN (2) results in changes in sympathetic discharge, hormone levels, and hepatic glucose output qualitatively similar to those seen during exercise.
The present study was designed to test the hypothesis that the carotid bodies, or receptors near this site, play a role in initiating the neuroendocrine response and maintaining arterial glucose homeostasis during exercise. To examine the role of the carotid bodies, or receptors anatomically near the site, carotid body-resected (CBR) conscious dogs or dogs having undergone a sham surgery (Sham) were studied in the basal state and during 150 min of moderate-intensity treadmill exercise. Isotope-dilution methods were used to calculate glucose kinetics.
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MATERIALS AND METHODS |
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Animal maintenance and surgical procedures. Mongrel dogs (n = 12, 23.9 ± 0.6 kg body wt) of either gender that had been fed a standard diet (Pedigree Choice Cuts, Vernon, CA; LabDiet, PMI Nutrition International, St. Louis, MO) were studied. The dogs were housed in a facility that met American Association for the Accreditation of Laboratory Animal Care guidelines, and the protocols were approved by the Vanderbilt University Animal Care and Use Committee. At least 16 days before each experiment, a laparotomy was performed under general anesthesia (1-2% isoflurane). Silastic catheters (0.03 in. ID) were inserted into the vena cava for subsequent tracer ([3-3H]glucose) and indocyanine green (ICG) infusion. Silastic catheters (0.04 in. ID) were also inserted into the portal vein, left common hepatic vein, and iliac artery for subsequent blood sampling. After insertion, all catheters were filled with saline containing heparin (200 U/ml; Abbott Laboratories, North Chicago, IL), and their free ends were knotted.
Ultrasound blood flow probes (Transonic Systems, Ithaca, NY) were used to measure portal vein and hepatic artery blood flow (19). The portal vein and hepatic artery were accessed from the abdominal incision and fitted with 6.0- and 3.0-mm-ID flow probe cuffs, which were then secured around the vessels. Catheters and the Doppler probe leads were placed under the skin at the incision site. An 8-cm ventral midline incision was made 1 cm proximal to the mylohyoideus muscle and extended 8 cm distally. Blunt dissection was used to expose the left and right common carotid arteries at the point of their bifurcation into the external and internal branches. The tissue at the carotid sinus in which the carotid bodies were thought to lie was identified and excised. However, because the carotid bodies are difficult to visualize, associated nerves supplying the skeletonized area were transected to ensure that if carotid body tissue remained, it would not be able to transmit signals to the brain. Segments (1 cm) of the common carotid and each branch were skeletonized and cleared of all tissue. Care was taken not to disrupt the occipital, cranial, laryngeal, or other arterial branches close to the site. To ensure disruption of all neural tissue, the skeletonized areas were swabbed with alcohol (19). After the closure of the incision sites, the effectiveness of carotid body removal was verified by the absence of a ventilatory response to NaCN (20-40 µg/kg). Starting 1 wk after surgery, dogs were accustomed to running on a motorized treadmill regardless of whether they were used for sedentary or exercise experiments. Animals were not exercised during the 48 h preceding an experiment. Only animals that had 1) a leukocyte count <18,000/mm3, 2) a hematocrit >36%, 3) normal stools, and 4) a good appetite (consuming the entire daily ration) were used for experiments. Studies were conducted after an 18-h fast, because dogs are postabsorptive after this interval. On the day of the experiment, the subcutaneous ends of the catheters and flow probes were freed from subcutaneous pockets through small skin incisions made under local anesthesia (2% lidocaine; Astra Pharmaceutical Products, Worcester, MA). The contents of each catheter were aspirated, and the catheters were flushed with saline. Saline was infused in the arterial catheter throughout the experiments (0.1 ml/min).Experimental procedures.
Experiments consisted of a tracer equilibration period (120 to
40
min), a basal sampling period (
40 to 0 min), and a period of
moderate-intensity (100 m/min, 12% grade) treadmill exercise (0-150 min). A primed (42 µCi) infusion (0.30 µCi/min) of
[3-3H]glucose (specific activity 20 Ci/mmol) was
initiated at
120 min. The infusion was increased by 80, 100, 120, and
140% of the basal infusion rate from 0 to 10, 10 to 20, 20 to 30, and
30 to 120 min, respectively. The aim of this infusion protocol
was to minimize changes in [3-3H]glucose specific
activity. An infusion of ICG (0.1 mg · m
2 · min
1) was
initiated at this time. Arterial samples were drawn at 10-min intervals
from
40 to 150 min. Portal and hepatic vein samples were drawn at
40,
20, 0, 10, 30, 50, 60, 80, 100, 110, 130, and 150 min. The
exercise intensity used in these experiments has been shown to result
in a twofold increase in heart rate (24), an increase in
O2 uptake to ~50% of maximum (16), and an
~70% fall in liver glycogen (25). Hepatic artery and
portal vein blood flow were recorded continuously from the frequency
shifts of the pulsed sound signal emitted from the blood flow probes (19). Heart rate and blood pressure were monitored
throughout all studies. Arterial blood gases were determined at
30,
50, and 120 min.
Processing of blood samples. Plasma glucose levels were determined by the glucose oxidase method using a glucose analyzer (Glucose Analyzer 2, Beckman Instruments, Fullerton, CA). For the determination of plasma [3H]glucose radioactivity, samples were deproteinized with barium hydroxide (Sigma Diagnostics, St. Louis, MO) and zinc sulfate (Sigma Diagnostics) on the day of the study. Samples were centrifuged, and the supernatant was evaporated and reconstituted in 1 ml of water and 10 ml of Ecolite+ (ICN, Irvine, CA). Radioactivity was then determined by liquid scintillation counting using a Beckman LS-5000TD instrument. ICG concentration was measured spectrophotometrically (805 nm) in arterial and hepatic vein plasma immediately after experiments. Plasma nonesterified fatty acids were measured spectrophotometrically using the kit made by Wako Chemicals (Richmond, VA). Whole blood lactate, alanine, and glycerol concentrations were determined in samples deproteinized with a 1:3 volume of 4% perchloric acid by enzymatic methods (12) on a Monarch 2000 centrifugal analyzer (Instrumentation Laboratories, Lexington, MA). An acid-base analyzer (model ABL30, Radiometer, Copenhagen, Denmark) was used for determination of arterial blood gases and pH. Corrections were made between the temperature setting of the analyzer and the body temperature of the dogs.
Immunoreactive insulin was measured using a double-antibody system [interassay coefficient of variation (CV) = 10%]. Immunoreactive glucagon was measured in plasma samples containing 50 µl of 500 kallikrein-inactivating units of Trasylol per milliliter (Bayer, Kankakee, IL) using a double-antibody system (interassay CV = 7%) modified from the method developed for insulin. Plasma norepinephrine and epinephrine levels were determined using a high-performance liquid chromatography technique (interassay CV = 11 and 13%, respectively). Plasma cortisol was measured using the Coat-A-Count cortisol radioimmunoassay kit (Diagnostic Products, Los Angels, CA; interassay CV = 6%). The methods used for hormone analyses by this laboratory have been described previously (5).Materials. High-performance liquid chromatography-purified [3-3H]glucose was obtained from New England Nuclear (Boston, MA). ICG was purchased from Sigma Chemical (St. Louis, MO). Standard glucagon, 125I-glucagon, glucagon, insulin antisera, standard insulin, and 125I-insulin were obtained from Linco Research (St. Louis, MO). Enzymes used in chemical analyses were obtained from Sigma Pharmaceuticals (St. Louis, MO) or Boehringer Mannheim Biochemicals.
Calculations.
Total glucose appearance (Ra,
mg · kg1 · min
1) and
disappearance (Rd,
mg · kg
1 · min
1) were
determined using the two-compartment model described by Mari
(14) for non-steady state with [3-3H]glucose
as the tracer. The isotope infusion was increased with exercise. This
minimized the change in specific activity caused by the increased
release of glucose from the liver and, thereby, the model dependency of
the Ra calculation.
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RESULTS |
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Basal arterial blood gases, blood pressures, and hematocrit. PCO2 was significantly elevated in CBR (41 ± 3 mmHg) compared with Sham (33 ± 1 mmHg), while PO2 was reduced (82 ± 9 and 103 ± 6 mmHg in CBR and Sham, respectively). Renal compensation for the hypercapnia was effective, inasmuch as pH was equivalent in the two groups (7.39 ± 0.01 and 7.38 ± 0.02 in CBR and Sham, respectively). Systolic and diastolic blood pressures were 164 ± 13 and 85 ± 7 mmHg in CBR and 145 ± 10 and 84 ± 3 mmHg in Sham. Heart rate was 90 ± 6 and 91 ± 6 beats/min in CBR and Sham, respectively. Hematocrit was 0.38 ± 0.01 and 0.38 ± 0.01 at rest in CBR and Sham, respectively, and 0.39 ± 0.02 and 0.41 ± 0.01 during exercise. There were no significant differences in blood pressure, heart rate, or hematocrit between the two groups.
Arterial plasma glucagon and insulin.
Figure 1 shows changes in arterial plasma
glucagon and insulin from basal. Insulin was equal in the basal period
in Sham (8 ± 1 µU/ml) and CBR (7 ± 1 µU/ml), and
concentrations decreased similarly during exercise. Basal arterial
glucagon was reduced in CBR compared with Sham (29 ± 3 vs.
47 ± 3 pg/ml). During exercise, the glucagon increase was greater
in Sham than in CBR (increase of 47 ± 9 vs. 15 ± 2 pg/ml).
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Arterial plasma cortisol and catecholamine responses.
Figure 2 shows arterial plasma cortisol.
Basal cortisol was not significantly different in Sham and CBR.
Arterial cortisol tended to increase higher in Sham than in CBR after
60 min of exercise, but differences were not significant. Figure
3 shows arterial plasma norepinephrine
and epinephrine concentrations. Basal norepinephrine and epinephrine
were similar in CBR and Sham. During exercise, norepinephrine increased
by 432 ± 124 pg/ml in Sham, but by only 201 ± 28 pg/ml in
CBR (P < 0.05). Arterial epinephrine responses to
exercise were similar in Sham and CBR.
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Arterial plasma glucose and glucose kinetics.
Arterial plasma glucose was similar in the basal period in Sham and CBR
(105 ± 2 and 108 ± 2 mg/dl, respectively). Figure 4 shows exercise-induced changes in
arterial plasma glucose from basal. Arterial glucose was not
significantly changed in Sham (decreased by 3 ± 2 mg/dl) but
dropped by 10 ± 3 mg/dl at the onset of exercise in CBR. The
difference in arterial glucose was sustained for the first 100 min of
exercise.
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Arterial concentrations and net hepatic balances of alanine, glycerol, lactate, and free fatty acids. Table 1 shows that there were no significant differences in arterial concentrations or net hepatic balances of alanine, lactate, glycerol, and free fatty acids in the basal state or during the exercise period.
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DISCUSSION |
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The results of this study clearly show that, in the absence of
functional carotid bodies and possibly other carotid sinus receptors,
the arterial plasma glucagon and norepinephrine responses to exercise
are blunted. The exercise-induced rise in arterial norepinephrine in
CBR dogs was only 50% of the response in Sham dogs. Because arterial
epinephrine concentrations were unaffected by the resection procedure,
it is reasonable to assume that the reduction in norepinephrine levels
is due to a reduction in sympathetic discharge. The precise tissue bed
in which the reduction in sympathetic activity occurs is impossible to
determine from these data. Because of the magnitude of the attenuation
of the norepinephrine response, it is probable that sympathetic
activity to multiple tissues is involved. As we demonstrated
previously, CBR reduced basal glucagon concentration (11).
Here we showed that the exercise-induced increment in arterial glucagon
in CBR dogs was only 30% of the response in Sham dogs. One cannot rule
out that the impairment in the increases in sympathetic activity and
arterial glucagon is linked, so that an impaired sympathetic nervous
response leads to decreased pancreatic -cell glucagon release. We
recently showed that the increase in net splanchnic release of glucagon
with exercise occurs even after the pancreas has been denervated
(7). Of course, this finding may be specific to pancreata
that have been denervated chronically and may not apply to animals with
an intact nerve supply to the pancreas. Another possibility is that it
is the increment in circulating norepinephrine that is controlling the
glucagon response, and it is the reduction in this variable that
results in the attenuated glucagon response to exercise. The results of
the present studies are consistent with the demonstration that the
response to hypoxia, which is mediated by the carotid bodies, is
characterized by activation of the neuroendocrine system (27). Moreover, they are consistent with the demonstration
that inhalation of 100% O2, which diminishes the
electrical activity of carotid body afferents (15),
attenuates the exercise-induced increase in norepinephrine
(8).
It is conceivable that the impaired hypoglycemia- (11) and
exercise-induced glucagon levels occur not as a result of impaired sensing of a blood signal due to the absence of the carotid bodies or
receptors nearby, but as a result of an impaired capacity of the
-cell to produce or secrete the hormone. Although we could find no
direct evidence in the literature to indicate that this should be
expected, the presence of the chronic reduction in basal glucagon would
be consistent with an adaptation of the
-cell that resulted in
impaired glucagon synthesis or secretion. The possibility exists that
the procedure alters a neural or chemical signal to the
-cell that
chronically alters its function. The same possibility also exists for
the exercise-impaired norepinephrine response. It should be noted,
however, that basal concentrations and the capacity to increase
norepinephrine in response to hypoglycemia are normal after CBR
(11).
We recently showed that CBR dogs have an impaired glucoregulatory
response to insulin-induced hypoglycemia. Although Ra rose by ~2 mg · kg1 · min
1 in
response to moderate hypoglycemia (~65 mg/dl) in Sham dogs, it did
not respond to hypoglycemia in CBR dogs. Compared with the response to
hypoglycemia, the effect of CBR on glucoregulation during exercise was
much more subtle. Arterial plasma glucose fell by ~10 mg/dl at the
onset of exercise in CBR (first sample was 10 min after exercise
onset), while it was essentially unchanged in Sham. The arterial
glucose was reduced for the remainder of the exercise period with
respect to basal values. Interestingly, the effect of CBR on regulation
of arterial glucose is essentially the same as it is with regulation of
arterial PCO2. Human subjects treated for
asthma by surgical removal of their carotid bodies exhibit dissociation
between CO2 production and ventilation, which results in a
larger excursion in arterial PCO2 than in
healthy controls at the onset of exercise (26). The
resulting hypercapnia was sustained in CBR subjects for the remainder
of the exercise period. So with the regulation of arterial glucose and
arterial PCO2, there is mismatching of release
and removal of these compounds, which results in a small deviation from
resting values. Other mechanisms or compensation for the absence of
carotid bodies become important during steady-state exercise as the
mismatching is corrected, and there is no further deviation in these variables.
CBR resulted in only a small transient deviation in arterial glucose.
Even very small, essentially undetectable changes in arterial glucose
can elicit compensation that may mask a primary deficit in
glucoregulation (5, 9, 10, 22, 23). This was exemplified
by an experiment in which a reduction in arterial plasma glucose of 6 mg/dl due to a low-dose intraportal insulin infusion resulted in a peak
compensatory Ra response of ~4
mg · kg1 · min
1 in the
exercising dog (22). In a second study, it was shown that
cessation of a glucose infusion that completely prevented the
exercise-induced rise in Ra resulted in a small drop in
arterial plasma glucose of ~5 mg/dl, which led to a compensatory
increase in Ra of ~4
mg · kg
1 · min
1
(5). One remarkable result of the latter study was that
full compensation was essentially present 2.5 min after cessation of the glucose infusion. The glucoregulatory system is sufficiently sensitive and responds with enough rapidity to a decrement in blood
glucose during exercise to prevent a more pronounced drop in blood
glucose. Clearly, however, if compensation were present here, it would
have to be due to sensing at a site other than the carotid bodies
(e.g., liver or brain).
Our previous work showed that the increase in glucagon is a major determinant of the increment in Ra during exercise (20). For this reason, it was surprising that the impaired glucagon response did not result in a greater deficit in Ra and NHGO. There was a tendency for reduced Ra and NHGO in CBR compared with Sham; however, differences were not significant. Thus even the reduced glucagon response seen in CBR appears to be largely adequate for the stimulation of Ra during exercise. It is possible that the small decrease in glucose heightens the responsiveness of the liver to glucagon. Perhaps the tonic reduction in glucagon that resulted from the resection procedure resulted in upregulation of hepatic glucagon receptors (1, 17) or signaling molecules.
If, in fact, carotid body function is necessary for the full neuroendocrine response to exercise, the issue then becomes the signal or signals that they are sensing. It is well known that the carotid bodies are sensitive to pH, PO2, and PCO2. More recently, it has been shown that they are sensitive to glucose (3, 4, 11). The signal sensed by the carotid bodies that stimulates the neuroendocrine response to exercise is impossible to elucidate from these studies. It is important to recognize that if it is responding to blood gases or glucose, the signal can be transmitted without a measurable error signal, inasmuch as these variables are generally unchanged during moderate exercise. It is important to appreciate that although the experimental sampling frequency is finite and varies, the body samples arterial blood continuously and is considerably more apt to detect oscillations or rapid changes over time.
Sympathetic nerve stimulation is the primary means of increasing lipolysis during exercise (21). Despite the attenuation of the exercise-induced increase in arterial norepinephrine by CBR, and presumably sympathetic nerve activity, arterial glycerol and nonesterified fatty acid levels were not significantly blunted. Apparently, the attenuated increase in sympathetic drive was still adequate, sympathetic drive to adipose tissue was not affected, or compensation for the deficit in sympathetic activity was present.
The carotid bodies are difficult to visualize in the dog. Therefore, we took the precaution of denervating the region immediately surrounding the tissue where the carotid bodies were presumed to lie as added insurance that no signal from the carotid bodies was transmitted to the central nervous system. The absence of a pulmonary response to intravenous NaCN injection in CBR confirmed that the procedure was successful. A consequence of the surgical procedures in CBR is the likelihood that all or some of the innervation to baroreceptors in the carotid sinus, as well as in the carotid bodies, was removed. Resting arterial systolic and diastolic blood pressures were similar in CBR and Sham, suggesting that compensation for the removal of any baroreceptors was effective. It is also important to note that, because of the difficulty of aortic glomectomy, the aortic bodies, which are believed to play a minor role in regulation of blood gases, at least, were left intact. One cannot rule out that aortic chemoreceptors play a role in neuroendocrine regulation.
Arterial PO2 and PCO2 were 82 and 41 mmHg, respectively, in CBR. The reduced PO2 and elevated PCO2 are added confirmation that the carotid bodies were no longer effective (13). Arterial pH was similar in CBR and Sham, indicating that renal compensation for the greater retention of CO2 was complete. It is unlikely that changes in blood gas concentration affected the neuroendocrine or glucoregulatory responses to exercise. In a previous study, we examined the effects of decreasing arterial PO2 on liver and muscle glucose metabolism and whole body glucose fluxes in the dog (27). Arterial PO2 had no effect on glucose metabolism until it was <60 mmHg. Moreover, decreased arterial PO2 tends to increase glucagon and norepinephrine levels and not diminish the response, as seen during exercise in CBR (27).
In summary, these studies suggest that input from the carotid bodies, or receptors anatomically close to them, 1) play a role in the neuroendocrine response to exercise and 2) participate in the non-steady-state coupling of Ra to Rd but 3) are not essential to glucoregulation during sustained exercise. These results support the notion that carotid body function is not restricted to blood gas regulation but may also play a role in neuroendocrine function.
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ACKNOWLEDGEMENTS |
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We are grateful to Deanna Bracy, Wanda Snead, Eric Allen, and Angelina Penaloza for excellent technical assistance.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-50277. Y. Koyama was a recipient of a Postdoctoral Fellowship Award from the American Heart Association, Southeast Affiliate.
Address for reprint requests and other correspondence: Y. Koyama, Dept. of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Light Hall Rm. 702, Nashville, TN 37232-0615.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 26 September 2000; accepted in final form 17 May 2001.
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