Under second-year coach Rick Pitino, who has pumped life back into the program, the Cardinals (10-1, 2-0 C-USA American) are off to their best start since going 15-1 in 1996-97.
For the third time this season, the Cardinals overcame a halftime deficit before rolling after intermission. Louisville trailed by two at the half, but took over in the final 20 minutes with Gaines leading the way.
Anthony Drejaj scored 16 points to lead St. Louis (6-7), which has three losses against ranked teams this season.
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