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1. Run it up the gut. Indianapolis has transitioned from a Tampa-2 defense to a 3-4 scheme with mediocre results. The Colts are allowing 120 rushing yards per game and have been particularly vulnerable up the middle. Nose tackle Antonio Johnson, who checks in at 310 pounds, isn’t the ideal run plugger in the middle of the defense. Inside linebackers Kavell Conner (6-foot, 243 pounds) and Jerrell Freeman (6-0, 234) are somewhat undersized, as well. The Bills’ new starting running back, C.J. Spiller, has carried 50 times this season up the middle, for 376 yards (an average of 7.5 per rush). Fred Jackson has 29 carries for 126 yards, an average of 4.3 per rush. The Bills should have success lining up behind center Eric Wood and left guard Andy Levitre and running the rock.

2. Get another big play from Leodis. The Bills’ biggest statistical advantage will come when the Colts punt the ball. Indianapolis’ punt coverage unit ranks 30th in the NFL, allowing an average of 13.7 yards per return. Leodis McKelvin remains the NFL’s leader in punt return average at 21.9 yards, with two of the three longest punt returns of the season, covering 88 and 78 yards (both of which were touchdowns). He’s also the clubhouse leader for quote of the year, when he said after the victory against Miami that he’s always a threat to “take one to the crib.” He’s right. McKelvin has a league-best seven returns of 20-plus yards, and is electrifying with the ball in his hands.

3. Keep an eye, or two, on Reggie Wayne. Bills rookie cornerback Stephon Gilmore has assumed the job of defending the other team’s No. 1 receiver. That means he’ll be following Reggie Wayne today. The Colts’ veteran receiver leads the NFL in receptions (76) and targets (130) and is second in yardage (1,003). His eighth 1,000-yard season has matched Marvin Harrison’s team record and made Wayne the 13th player in NFL history to pass the milestone with such frequency. The Bills might have to give Gilmore some help to stop Wayne.

4. Cash in against nickel. The Indianapolis secondary does not feature a ball hawk. The Colts have just four interceptions, tied for fewest in the NFL. If Vontae Davis isn’t 100 percent because of a knee injury, the Colts will turn to Cassius Vaughn and Darius Butler as starting cornerbacks, along with Josh Gordy at the nickel. Against New England last week, those three gave up a combined passer rating of 138.1, according to Pro Football Focus.

5. Silence the home crowd. Lucas Oil Stadium, where the Bills have never played, can be one of the loudest in the NFL, and today’s game is a sellout. The Colts are 4-1 at home, where they do a much better job of taking care of the ball (just three turnovers in those five games). They’ve harnessed the emotion that has come from head coach Chuck Pagano’s battle with leukemia in a positive way, playing inspired football. The best way for a road team to take the home crowd out of the game is to jump out to an early lead and get stops on defense. That will be a big challenge for the Bills today. The Colts rank fourth in third-down conversions, making first downs 44.9 percent of the time, while the Bills are 31st in the NFL in third down stops, giving up first downs 46 percent of the time.

Outlook: Bills safety George Wilson said this week the playoffs have started for his team. He’s right, in the sense the Bills will all but be eliminated with a loss today. The thinking here is that won’t happen. It’s time for a meaningful road win.

Prediction: Bills 27, Colts 24