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Savage threw for a career-high 424 yards on 23-of-33 passing with three scoring passes to freshman Tyler Boyd.
The Panthers (2-1, 1-1) never trailed and claimed their first ACC victory despite receiving plenty of scares down the stretch from a persistent Duke team.
Brandon Connette had four touchdown passes and four interceptions, and he rushed for 101 yards and two touchdowns for Duke (2-2, 0-2).
Connette's 4-yard touchdown run with 3:17 left pulled the Blue Devils within three. Pitt recovered the onside kick, and Savage's 15-yard pass to Kevin Weatherspoon on third-and-7 helped the Panthers run out the clock.
The teams combined for 1,130 total yards.