Learning ability in young rats with single and double lesions to the “general learning system”

Physiology & Behavior,Vol. 45, pp. 133-144. Copyright©Pergamon Press pie, 1989. Printed in the U.S.A.

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Learning Ability in Young Rats With Single and Double Lesions to the "General Learning System" JEN YU, ROBERT THOMPSON, PETER W. HUESTIS, V I C T O R M. B J E L A J A C A N D F R A N C I S M. C R I N E L L A

Department o f Physical Medicine and Rehabilitation, University of California Irvine Medical Center Orange, CA 92668 and State Developmental Research Institutes, Costa Mesa, CA 92626 R e c e i v e d 16 M a y 1988 YU, J., R. THOMPSON, P. W. HUESTIS, V. M. BJELAJAC AND F. M. CRINELLA. Learning ability in young rats with single and double lesions to the "generallearning system." PHYSIOL BEHAV 45(1) 133-144, 1989.--Previous lesion studies suggest that the dorsal caudatoputamen (DCP), globus pallidus, ventrolateral thalamus (VLT), substantia nigra, ventral tegmental area, superior colliculus (SC), median raphe, and pontine reticular formation are components of the general learning system (GLS) of the rat brain. The current study attempted to determine whether bilateral lesions to two components of the GLS (DCP/VLT, DCP/SC or VLT/SC) would produce greater deterioration of learning ability than bilateral lesions to only one component (DCP, VLT or SC). In all combinations examined, a second lesion added to the first led to a significantly greater learning decrement on a series of spatial reversal problems than that associated with the first lesion alone. These results are compatible with the view that the foregoing structures are elements of the same functional system concerned either directly or indirectly with general learning ability. Learning ability

Single lesions

Double lesions

General learning system

R E C E N T findings on young brain-damaged rats suggest that normal acquisition of most problem-solving activities requires the integrity o f both a nonspecific mechanism (a group o f brain structures participating in the learning of a broad spectrum of laboratory tasks) and one or more specific mechanisms (brain structures participating in the learning of a particular class of laboratory tasks). F o r example, the frontal (sensorimotor) cortex and mediodorsal thalamus o f the rat brain would appear to be components of a specific mechanism concerned with motor skill learning since damage to either structure alone impairs acquisition of various latchbox problems (21,22), while leaving intact the ability to acquire a visual (white-black) discrimination p r o b l e m (18). On the other hand, the regions o f the dorsal caudatoputamen, giobus pallidus, ventrolateral thalamus, substantia nigra, ventral tegmental area, superior colliculus, median raphe and pontine reticular formation may be components of a nonspecific mechanism as evidenced by the fact that selective damage to these subcortical structures impairs not only motor skill and visual discrimination learning (20, 23, 24), but maze, nonvisual discrimination, and detour learning as well (23,24). The function o f this nonspecific mechanism, which will be termed the "general learning s y s t e m " (GLS) for convenience in exposition, is uncertain. Although other interpretations are possible (each component of the GLS contributes in a specialized way to the learning process), we favor the notion that the combined activities o f the GLS are

responsible for a unitary, though broad, function in learning, possibly one related to the setting and sequencing of activities of particular brain regions for the task at hand (24). The purpose of the present study was to determine whether bilateral lesions to two components of the GLS would produce greater deterioration of learning ability than bilateral lesions to only one component. In terms of our conceptualization of the G L S as having a unitary function in the domain of " e x e c u t i v e " processes, double (multiple) lesions would be expected to lead to more severe learning deficits than single lesions. It should be emphasized at the outset that confirmation of this prediction would not necessarily constitute a trivial finding in the sense that it would be counterintuitive to expect that multiple brain lesions would have equivalent or lesser effects on learning relative to single lesions. There now appear to be enough studies within the experimental and clinical literature reporting unexpected outcomes of multiple versus single (and large versus small) lesions to raise serious doubts about the generality of a mass action effect when applied to combination lesions, particularly those involving subcortical formations (5). F o r example, it has been observed in laboratory animals that a second (or third) lesion added to an initial lesion may not intensify a learning deficit (1,15) and may even reinstate, at least in part, a learned response that was abolished by the initial lesion (3, 8, 9, 11, 16, 17, 28). Furthermore, learning ability in cats may not necessarily suffer in proportion to the number of subcor-

133

134

~ 1 t:'1 4 t .

tical areas (up to seven) damaged (4, 6, 7). Recently, we found that an amygdaloid lesion superimposed upon a hippocampal lesion in adult rats is not associated with a greater spatial reversal learning impairment or more rapid forgetting of individual spatial reversal problems than damage to the hippocampus alone (unpublished study). [These findings, our course, contrast with those (12,13) in which combined hippocampal-amygdaloid lesions in monkeys induced a greater learning disturbance on a delayed nonmatching-tosample task than either a hippocampal or amygdaloid lesion alone.] In a similar vein, rats sustaining combined lesions to the fornix and amygdala have been reported to be unimpaired in both original and reversal learning of olfactory discrimination problems (2). F o r practical considerations, the dorsal caudatoputamen (DCP), ventrolateral thalamic complex (VLT), and superior colliculus (SC) were selected from among the eight components of the GLS for this study. The remaining five components were not investigated because of the possibility that a second lesion superimposed upon a lesion of either the globus pallidus, substantia nigra, ventral tegmental area, median raphe, or pontine reticular formation would result in an intolerably low survival rate. (Even with the choice of the DCP, VLT, and SC, it was necessary to make smaller lesions than usual in order to assure a reasonably high survival rate among the rats with double lesions.) Weanling (rather than adolescent or adult) rats were prepared with these brain lesions inasmuch as the current composition of the GLS is almost entirely based upon the investigation of early brain damage (23,24). An important methodological decision that had to be made concerned the type of laboratory task that would serve as an index of learning ability. Tasks based upon an appetitive motive were unacceptable since it was not expected that young rats with multiple lesions to the GLS would endure prolonged periods of food/water deprivation. Similarly, tasks based upon the motive of escape-avoidance of foot shock were deemed unsuitable owing to the possibility that rats with multiple lesions would either require an excessive number of shocks to force escape-avoidance responses or exhibit frequent "ballistic" running responses to single shocks. Under the circumstances, a water task seemed to be a reasonable choice. Spatial reversal problems were specifically studied not only because they are highly sensitive to the presence of brain damage (19), but because they are of moderate difficulty, a feature which would reduce the influences of "ceiling" and " f l o o r " effects that could complicate comparisons between subjects with mildly impaired (single lesions) and severely impaired (multiple lesions) learning ability (29). Specifically, weanling rats subjected to either sham operations (controls), selective bilateral lesions to the DCP, VLT, and SC, or multiple bilateral lesions (the combinations included DCP/VLT, DCP/SC, and VLT/SC) were rested for three weeks and subsequently trained on a series of four spatial reversal problems. In view of the likelihood that the double-lesioned groups might be more active than the single-lesioned groups (which would raise the possibility that any differences in learning ability might be a secondary consequence of hyperactivity), an activity test was administered prior to training on the reversal problems. METHOD

Subjects and Surgery Weanling (22-26-day-old) male Sprague-Dawley albino

rats (55-65 g) underwent surgery under deep chloa al hydrate anesthesia (400 mg/kg). The lesions in all six experimental groups were accomplished (in one stage) stereotaxically by passing a constant anodal current of 1.0 mA for a duration of 5-8 sec through an implanted stainless steel electrode (0.5 mm in diameter) with 1.0 mm of the tip exposed. One of these groups (Group DCP) sustained bilateral lesions to the dorsal caudatoputamen at intermediate frontal levels twith the head of the rat oriented horizontally in the stereotaxic headholder, the coordinates were 7.5 mm anterior to lambda, 2.0 and 3.0 mm lateral to the longitudinal sinus, and 4.5 mm ventral from the surface of the brain). The second group (Group VLT) received bilateral lesions to the region of the ventrolateral thalamus (5.25 mm anterior, 1.9 mm lateral, and 6.0 mm ventral) and the third (Group SC) was subjected to bilateral lesions to the superior coUiculus (1.75 mm anterior, 1.0 and 2.0 mm lateral, and 4.25 mm ventral). The remaining three experimental groups (Groups DCP/VLT, DCP/SC, and VLT/SC) received lesions to two of the three foregoing structures, the stereotaxic coordinates and lesion parameters being the same as those employed for the production of the corresponding single lesions. The last group (Group C) served as operated controls, undergoing the same surgical procedure as the experimental groups, save for drilling of the skull and lesioning of the brain. Following surgery, the animals were usually housed, two or three per cage, in medium-size hanging wire cages containing a constant supply of food pellets and water. A dish of sweetened wet mash was placed daily in each cage during the first postoperative week to encourage early resumption of food intake. During the third postoperative week, the animals were handled daily for approximately 5 min. During this handling period and the subsequent period devoted to behavioral testing, the experimenters were given no knowledge as to which group each subject belonged. All animals were maintained on a 12-hr light-dark cycle with lights on at 0600 and were tested only during the light phase.

Apparatus Activio, box. Activity was measured in an enclosed rectangular box (90x64x30 cm) painted flat black and covered with a smoked Lexan lid. By means of luminous paint, an iridescent grid pattern consisting of 12, 21:5 cm squares was inscribed on the floor of the box. Observations were made in a semidarkened room. Water maze. The water maze consisted of a 296 liter glass tank measuring 122x42×50 cm filled with tap water (about 20°C) to a depth of 32 cm. It was essentially divided into a start area, choice chamber, and left and right terminal areas (see Fig. 1). An interchangeable submerged escape platform (16.5x 16.5x30 cm) with a grid pattern etched on the top surface could be positioned at the far end of either the left or right terminal area. The water, which was made opaque by the addition of 25 cc of a liquid whitener (paste food color made by Chefmaster, Irvine, CA 92714), was routinely cleared of any debris. The tank was cleaned and the water and additive changed every five days. Located immediately behind the far end of the tank was a drying box (31 x 46 x 50 cm) made of smoked Lexan and containing a perforated floor. A blow dryer mounted 36 cm above the floor directed warm air toward the bottom of the box. Procedure Activity test. Following a three week recovery period, the

SINGLE AND DOUBLE LESIONS

DRYING CAGE

135 The specific training procedure was as follows: The rat was placed in the start area, facing away from the terminal areas. An error consisted of entering the incorrect (preferred) terminal area by at least the length of the animal's head and thorax. In order to escape from the water, the animal had to swim to the correct (nonpreferred) terminal area where the escape platform was located. After remaining on the platform for 5 sec, the animal was carried to the drying box to await the next trial. Total errors (initial errors combined with intratrial repetitive errors) were recorded on each trial. Reversal learning. On the day following original learning, the animals were started on a series of four reversal problems. The first reversal required the animal to choose the terminal area that was incorrect on original learning, the second reversal required the animal to choose the terminal area that was incorrect on the first reversal, etc. The training procedure was the same as that described in original learning. If an animal failed to learn a given reversal problem after having committed a total of 100 errors, training was discontinued and the final error score treated as though the animal reached the criterion at that point.

Histology

WATER HAZE FIG. I. Floor plan of the water maze showing the starting area (SB), choice chamber (CC), terminal areas (TA), escape platform (P), and drying cage.

At the conclusion of postoperative testing, each braindamaged animal was killed with an overdose o f chloral hydrate, its vascular system perfused with 10% formalin, and the brain removed and stored in 10% formalin for 2-4 days. Each brain was blocked, frozen, and sectioned frontally at 90 microns. Every third section through the lesions was subsequently photographed at 12× by using the section as a negative film in an enlarger.

Statistical Analyses

animals were weighed and then tested individually in the activity box. The animal was placed in the center of the floor and allowed to explore freely during one 5-min period. The number of squares entered by all four paws was recorded. (The number of rears made was also counted.)

The differences in mean error scores (and most other measures) between each brain-damaged group and the controls were evaluated by the Mann-Whitney U-test (twotailed), provided that the Kruskal-Wallis one-way analysis of variance applied to these data yielded an H which was significant at least at the 0.05 level.

Spatial reversals. Preliminary training. On the day following the activity test, the animals were started on preliminary training. During this phase of training, an escape platform was positioned at the far end of both the left and right terminal areas. A trial was initiated by placing the rat in the start area (facing away from the terminal areas) and was concluded when the animal swam across the choice chamber and mounted one of the escape platforms. The animal was forced to remain on the escape platform for 5 sec and then was transferred to the drying box to await the next trial. Usually, 10-11 trials were given with an intertrial interval of 30-60 sec. Choices of the left and right terminal areas were monitored in order to determine the preferred side for each animal. Throughout this experiment, the animals were run in squads of two or three. Original learning. Twenty-four hours later, training was begun on the original learning problem which involved choosing the nonpreferred side. A block of 8-16 trials was usually given each day with an intertrial interval of 30-60 sec. The criterion of learning consisted of the first appearance of a " p e r f e c t " or " n e a r - p e r f e c t " run o f correct responses having a probability of occurrence of less than 0.05 (14), followed by at least 75% correct responding in the subsequent block of eight trials given on the next day.

RESULTS

Mortality Rate and Discarded Subjects Of the original 92 weanling rats undergoing surgery, 21 died prior to the inception o f the activity test, the highest mortality rate occurring in Groups DCP/SC and VLT/SC. Four animals with double lesions were eliminated from the experiment because they were either unable to learn the original spatial discrimination problem within 150 errors or could not be shaped to swim efficiently to the escape platform. An additional 20 animals were discarded because their lesions were either to small, grossly asymmetrical, or distant from the intended target area(s). All of the remaining 47 braindamaged and control animals appeared healthy and alert by the end of the third postoperative week and displayed efficient escape behaviors in the water maze throughout the experiment.

Histology The dorsal caudatoputamenal lesions sustained by Groups DCP (Fig. 2), D C P N L T (Fig. 5), and DCP/SC (Fig. 6) were generally uniform in both topography and magnitude. This was also the case with respect to the ventrolat-

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SINGLE AND DOUBLE LESIONS

137

TABLE 1 WEIGHT (IN GRAMS),ACTIVITY(SQUARES ENTERED), A N D REARS FOR ALL GROUPS Weight

Activity

Rears

Group

N

Mean

Range

Mean

Range

Mean

Range

C DCP VLT SC DCP/VLT DCP/SC VLT/SC

10 7 7 6 5 7 5

176.1 167.6 165.3 157.7 149.2 141.1" 144.4"

135-200 140-184 157-177 112-180 103-180 111-176 103--167

89.6 80.4 92.9 78.0 106.0 108.3 119.4

37-139 72-97 74-109 3-139 86--127 72-184 70-178

15.8 9.7 14.1 7.2 10.4 2.9* 7.2

6-43 1-25 3-28 0-19 6-14 0-8 1-14

*Differs from controls at least at 0.05 level.

eral thalamic lesions received by Groups VLT (Fig. 3), DCP/VLT (Fig. 5), and VLT/SC (Fig. 7), although they did vary somewhat in location in the dorsal-ventral plane. The greatest variability occurred in the placement of lesions within the superior colliculus (Figs. 4, 6 and 7); at a given frontal level, the lesions either spared the superficial layers alone or destroyed major portions of the superficial and deeper layers.

Body Weight The mean (and range of) body weights of all groups after a three week recovery period are presented in Table 1. While all brain-damaged groups tended to be lighter than the controls, only Groups DCP/SC and VLT/SC showed a significant weight deficiency.

Reversal Learning Table 2 shows that while the groups with single lesions were not significantly impaired in learning the series of four reversal problems, all three groups with double lesions made significantly more errors on these problems than the controls. In fact, comparisons between the single- and corresponding double-lesioned groups revealed in every instance that the addition of a second lesion to the first significantly increased the error score relative to that associated with the first lesion alone. Parenthetically, two animals (one from Group CP/SC and one from Group VLT/SC) failed to learn the second reversal after having committed 100 errors, one (Group VLT/SC) failed to learn the third reversal, and one (Group CP/SC) failed to learn the fourth reversal; for statistical purposes, the total error scores of these animals were treated as though they had learned all four reversal problems.

Activity Table 1 also shows the activity scores for all groups. Although the majority of brain-damaged groups entered more squares than the controls during the 5-min test period, the Kruskall-Wallis one-way analysis of variance applied to these data yielded an H of 6 which fell considerably short of the 0.05 level of significance. On the other hand, the analysis of variance applied to the data on rearing responses yielded an H of 14 (df=6, p<0.05). As shown in Table 1, only Group DCP/SC made significantly fewer rearing responses than the controls.

Original Learning As noted in Table 2, the double-lesioned groups made more errors in original learning than either the singlelesioned groups or the controls. However, only Group VLT/SC was found to be significantly inferior to the controls in learning the initial spatial discrimination habit.

Other Comparisons To determine if the group with double lesions were impaired in reversal learning because of perseverative responding (repeatedly choosing the side that was correct on the immediately preceding problem), the total number of errors committed on a given reversal problem prior to the first appearance of a correct response was recorded for each animal. The mean number of such errors per reversal is referred to in Table 2 as the "perserveration index." It should be noted that the various groups were not remarkably different from each other with respect to this m e a s u r e - - a n H of less than 6 was obtained (df=6, p>0.30)----a finding which indicates that the reversal learning impairment manifested by the double-lesioned groups was not a reflection of excessive perseverative responding. In light of the foregoing negative results, it seemed reasonable to suppose that the impairment in reversal learning

FACING AND FOLLOWING PAGES FIG. 2. Photographs of unstained sections showing lesions in three rats of Group DCP. FIG. 3. Photographs of unstained sections showing lesions in three rats of Group VLT. FIG. 4. Photographs of unstained sections showing lesions in three rats of Group SC.

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SINGLE AND DOUBLE LESIONS

FIG. 4

139

YU t;7 A L

140

FIG. 5. Photographs of unstained sections showing lesions in one rat of Group DCP/VI.T.

TABLE 2 MEAN ORIGINAL LEARNING AND REVERSAL LEARNING ERRORS FOR ALL GROUPS Original

Reversal

Group

Mean

Range

Mean

Range

Perseveration Index

Inconsistency Index

C DCP VLT SC DCP/VLT DCP/SC VLT/SC

9.2 7.4 11.4 6.0 14.2 37.3 44.0*

1-27 2-16 2-22 2-17 4-28 6-132 3-127

30.3 35.4 25.3 35.0 68.2"t 99.3"t 83.4"t

15-88 14-72 13-43 9-82 42-119 34-219 36-131

3.8 4.0 3.3 2.8 3.9 6.0 2.2

0.3 0.4 0.4 0.7 1.7*t 2.7"t 2.1*t

*Differs from controls at least at the 0.05 level. tDiffers from corresponding single-lesioned groups at least at the 0.05 level.

SINGLE AND DOUBLE LESIONS

141

FIG. 6. Photographs of unstained sections showing lesions in one rat of Group DCP/SC.

observed in the double-lesioned groups was a product of inconsistent responding to the correct side during the precriteflon period. To evaluate this possibility, the data sheets of all animals were screened for a run of at least three consecutive correct responses followed by one or more errors during the precriterion period on each reversal problem. The mean number of such runs per reversal is referred to in Table 2 as the "inconsistency index." Inspection o f these data in Table 2 clearly supports the conclusion that the groups with double lesions were indeed significantly more inconsistent in responding to the correct side than were either the singlelesioned groups or the controls. DISCUSSION

It should be emphasized at the outset that considerable intersubject variance was present in all lesioned groups, par-

ticularly with respect to the learning scores shown in Table 2. In all likelihood, this was a reflection of variations in lesion topography. This factor may also account for the unusually high percentage of rats with multiple lesions that either died prior to the activity test or were eliminated from the experiment because of conspicuously poor performance on the original spatial discrimination problem. Unfortunately, analysis of the histological material failed to reveal any clues as to the anatomical basis for these individual differences. In spite of the relatively high degree of intersubject variability and the use of conservative statistical tests, reliable intergroup differences in performance on the learning problems emerged. The principle f'mding was that double lesions to the GLS produced significantly greater reversal learning deficits than corresponding single lesions. In all combinations examined, a second lesion added to the first led to a

142

~ ~i E l A L

FIG. 7. Photographs of unstained sections showing lesions in one rat or Group VLT/SC.

significantly greater reversal learning decrement than that associated with the first lesion alone. Parenthetically, it should be noted that two of the three groups with double lesions did not differ significantly from the controls in acquiring the original learning problem; this suggests that the former were not suffering from a posttraumatic "confusional state," nor were they incapable of storing information. Obviously, the foregoing data do not permit any categorical conclusions since only three of the eight components of the GLS were investigated, the number of animals composing each brain-damaged group was small, and only one test of learning ability was administered. Nevertheless, the overall pattern of results---double lesions, but not single lesions, impaired spatial reversal learning--confirms the prediction that learning ability in young rats suffers in proportion to the number of lesions (or the extent of damage) to the GLS.

One possible inconsistency concerns the absence of reversal learning deficit in Groups DCP, VLT, and SC. In earlier studies employing adult rats as subjects (19,25), bilateral damage to either DCP, VLT, or SC significantly impaired performance on a series of eight reversal problems in a T-maze adapted for the use of escape-avoidance o f foot shock as a motive. While this discrepancy could have arisen from differences in the age of the subjects or the nature o f the motivating condition, it is more likely a product o f variations in lesion magnitude. As noted at the outset of this study, it was necessary to reduce the size of the lesions in Groups DCP, VLT, and SC (by decreasing current intensity and duration from the customary 2.0 mA for 10 sec to 1.0 m A for 5-8 sec) in order to ensure a reasonably high survival rate in the double-lesioned groups. Another unexpected finding of this study pertains to the inconsistent performance of the double-lesioned groups on

SINGLE AND DOUBLE LESIONS

143

TABLE 3 PERCENTAGE OF ANIMALSWITHINEACH GROUPMANIFESTING AT LEAST ONE "INCONSISTENTRUN" DURING THE LEARNINGOF THE VISUALAND INCLINED PLANE DISCRIMINATIONPROBLEMS Inconsistent Run Group

N

Visual

Inclined Plane

Control Dorsal caudatoputamen Globus pallidus Ventrolateral thalamus Substantia nigra Ventral tegmental area Superior colliculus Median raphe Pontine reticular formation Parietal cortext

56 9 13 10 9 8 10 8 9 14

41.1 77.8* 61.5 50.0 88.9* 62.5 40.0 62.5 88.9* 71.4"

23.2 11.1 38.5 60.0* 66.7* 75.0* 70.0* 50.0 77.8* 42.8

*Differs from controls at least at the 0.05 level, Fisher exact probability (one-tailed) test. tThis structure is not a component of the GLS. These data were based on earlier experiments (23,24).

the spatial reversal problems. This was demonstrated by the finding that there were significantly more occasions in which the double-lesioned groups made one or more errors following a run of three consecutive correct responses than either the single-lesioned or control groups. This raises the possibility that difficulties in maintaining a set to execute the correct response is a prominent feature of the performance of rats with moderate damage to the GLS. To examine this possibility further, records were obtained from our files of animals with early lesions to the GLS (along with records of the corresponding sham-operated controls) that had been trained on both a visual (white versus black) and a nonvisual inclined plane (up versus down) discrimination problem. (These data were preferred to those derived from the previous study of spatial reversal learning in the

T-maze not only because the subjects received early, rather than late, lesions of the GLS, but because the criterion of learning was the same as, rather than different from, that used in the current experiment.) For these problems, the data sheets were screened for a run of at least four consecutive correct responses followed by one or more errors during the precriterion period. Table 3 shows the outcome of this analysis based upon the percentage of animals within each group that manifested at least one "inconsistent r u n " during the precriterion period. Interestingly, all groups with lesions to the GLS, except the globus pallidus and median raphe groups, differed significantly from the controls in the proportion of subjects manifesting an inconsistent run on at least one of the two problems. With respect to the two exceptions, it should be noted that the differences were in the expected direction, two of which almost reached statistical significance; the visual proportion in the case of the globus pallidus group (p =0.15) and the inclined plane proportion in the case of the median raphe group (p =0.12). However, it cannot be concluded that this kind of inconsistency is specific to rats with lesions in the GLS. For comparative purposes, we also examined the records of animals with early lesions to the parietal cortex that had been trained on the visual and inclined plane discrimination habits---although important for the acquisition of these discrimination habits (26), the parietal cortex is not essential for normal acquisition of puzzle-box problems (20) and, as a consequence, has been excluded from the GLS. As shown in Table 3, this group differed significantly from the controls in the proportion of subjects manifesting at least one inconsistent run during the learning of the visual habit; the difference in proportions associated with the inclined plane habit approached statistical significance (p =0.13). In view of these findings, it is clear that inconsistency in performance during the early stages of discrimination learning is not a feature unique to rats with lesions to the GLS, but rather may be a characteristic of most brain-damaged subjects that are deficient in learning problems of this sort. It remains to be determined, however, whether this type of inconsistent performance, which reflects difficulties in maintaining a set to execute the correct response, arises from a disturbance in either attentional (29) or inhibitory (10) mechanisms.

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